Transposition-based Therapies

Abstract

Gene therapy compositions and methods are provided that make use of novel transposases and/or chimeric transposases for targeted transposition.

Description

FIELD OF THE INVENTION

[0001] The present invention relates, in part, to a dual system using enzymes capable of transposition (e.g., engineered transposases and/or chimeric transposases) and transposons for targeting human genomic safe harbor sites (GSHS).

PRIORITY

[0002] The present application claims priority to and benefit from U.S. Provisional Patent Application No. 63/019,709, filed May 4, 2020, the U.S. Provisional Patent Application No. 63/027,561, filed May 20, 2020, U.S. Provisional Patent Application No. 63/058,200, filed Jul. 29, 2020, and U.S. Provisional Patent Application No. 63/175,345, filed Apr. 15, 2021, the entirety of each which is incorporated by reference herein.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] This application contains a Sequence Listing in ASCII format submitted electronically herewith via EFS-Web. The ASCII copy, created on May 3, 2021, is named SAL-003PC_ST25.txt and is 182,990 bytes in size. The Sequence Listing is incorporated herein by reference in its entirety.

BACKGROUND

[0004] Human gene therapy is a promising approach that delivers genes for treating and mitigating various diseases and conditions, including inherited and acquired diseases. Gene therapy involves replacing or complementing a mutated gene (which causes a disease) with a healthy copy of the gene, inactivating or silencing a mutated gene that is functioning improperly (or any other gene), or introducing a new gene into chromosomes. The ability to safely and efficiently integrate genes into a host genome is essential for successful gene therapy in humans.

[0005] Currently, the most commonly used vectors for permanent or transient transfer of genes in gene therapy trials are virus-based. Although it is possible to achieve stable genomic integration with high-efficiency using viral vectors, multiple studies have shown serious disadvantages and safety concerns. Thus, adenoviruses and adeno-associated viruses (AAV) have been shown to evoke host human responses that limit administration or re-administration, while retroviruses/lentiviruses preferentially integrate transgenes into euchromatin thereby increasing the risk of insertional mutagenesis or oncogenesis. Viral systems are also limited in cargo size, restricting the size and number of transgenes and their regulatory elements. Viral vector-host interaction can include immunogenicity, and integration of a viral vector DNA in a host genome may have genotoxic effects. Also, because the AAV genome mainly persists in an episomal form in the nucleus of the infected cells, it can be lost in conditions of cell proliferation (such as, e.g. liver growth or other organ growth), limiting therapeutic efficacy. Accordingly, limitations of viral vectors such as pathogenicity, expensive production, and systemic instability have proved to be major obstacles to the use of viral-based systems. In fact, re-administration of viral-based vectors can promote immune responses that can result in life threatening systemic effects and limit gene-transfer efficacy. See Kay et al. Proc Natl Acad Sci USA 1997; 94:4686-91; Hernandez et al., J Virol 1999; 73:8549-58.

[0006] Non-viral vectors (i.e., lipid-based, polymer-based, lipid-polymer based, and poly-lysine) are synthetic tools for encapsulating transgenic DNA or RNA until it reaches the cellular target. Compared to viral vectors, non-viral vectors are generally safer to prepare, and the risk of pathogenic and immunologic complications is diminished.

[0007] Non-viral vectors have been designed by modifying the surface of a non-viral vector for targeted therapy. See, e.g., Lestini et al., J Control Release 2002; 78:235-47.

[0008] Nucleases are also being evaluated for use in non-viral human gene therapy. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas9) and transcription activator-like effector (TALE) nuclease (TALEN) systems induce double-stranded DNA breaks (DSBs). The DSBs enhance homologous recombination to insert transgenes at specific sequences but off-target DNA cleavages at unknown remote sites cause inadvertent mutations that require complex genotoxicity screens for detection. The CRISPR system uses Cas9 complexed with a user-defined guide RNA (gRNA) to recognize and cut complementary sequences. TALEN and CRISPR both use host homology-directed repair to introduce a co-delivered donor template at the desired sequence. The TALEN and CRISPR approaches demonstrate efficient gene transfer, but concerns about their cyto- and genotoxic effects remain significant obstacles for clinical applications. Furthermore, gene addition using homology-directed repair requires replication, thus limiting nuclease technology to dividing tissues (i.e. not effective in non-diving tissue such as the central nervous system). Other gene editing techniques, such as prime editing and base pair editing, are limited to correcting base pairs or small nucleotide stretches. These features limit the in vivo and ex vivo application of this technology to diseases with a single common pathogenic nucleotide variant. However, most genetic disorders have hundreds or even thousands of pathogenic nucleotide variants in one or more genes.

[0009] A recombinase recognizes and binds specific sequences at the ends of a transposon, mediates synaptic interactions between the ends to bring them together, interacts with the target DNA, and executes the DNA breakage and joining reactions that underlie recombination. An integrase is a recombinase enzyme that is capable of integrating DNA (e.g., of a virus), into another piece of DNA, usually the host chromosome.

[0010] DNA transposons are mobile elements that use a "cut-and-paste" mechanism. DNA is excised by double strand cleavage from the donor molecule and integrated into the acceptor molecule. Transposons move from one position on DNA to a second position on DNA in the presence of a transposase, an enzyme that binds to the end of a transposon and catalyzes its movement to a specific genomic location in a host.

[0011] A main concern in transposase-based gene therapy is insertional mutagenesis due to random integration, albeit mostly at known sequences (e.g. TTAA (SEQ ID NO: 1) sequences), near or within loci that activate oncogenes, interrupt tumor-suppressor genes, or disrupt the transcription of normal genes. Thus, while non-viral, transposon gene therapy approaches have great promise for treating individuals with genetic disorders, the challenge is to reduce the risk of random insertion.

[0012] Accordingly, there is a clinical need to improve the safety of enzymes capable of transposition, such as, e.g., transposases, to reduce the risk of insertional mutagenesis and oncogenesis.

SUMMARY OF THE INVENTION

[0013] Therefore, the present invention provides, in part, novel transposase compositions that have particular use in therapies yet avoid limitations of existing transposases.

[0014] In aspects, there is provided a mammalian transposase which is suitable for use in gene therapy, and advantageously gene therapy with large payloads (e.g. a transposon) which is durable. In aspects, the mammalian transposase is an engineered version of an Myotis lucifugus transposase (MLT transposase) that has been designed to have an N-terminal amino acid substitution and C-terminal amino acid deletions. In embodiments, the MLT transposase has an amino acid sequence of SEQ ID NO: 2, or a variant thereof. In embodiments, the MLT transposase is further engineered to have amino acid substitutions to improve activity, e.g. at positions corresponding to positions S8, C13, and/or N125 of SEQ ID NO: 2.

[0015] In aspects, a composition is provided comprising a transposase enzyme (e.g., an MLT transposase) or nucleic acid encoding the transposase enzyme, wherein the transposase enzyme comprises an amino acid sequence having at least about 80% sequence identity to SEQ ID NO: 2, wherein the transposase enzyme comprises an amino acid substitution at the position corresponding to position S2 of SEQ ID NO: 2.

[0016] The present invention provides a gene transfer system or construct comprising a monomer or a head-to-tail dimer enzyme capable of genomic integration by transposition and a DNA binding domain (DBD), such as a transcription activator-like effector protein (TALE) DBD or inactive (dCas9) programmed by a guide RNA (gRNA) (referred to as a dCas9/gRNA complex) as shown in FIGS. 1A-D or in FIG. 2. These chimeric systems, having a DBD fused to an enzyme capable of transposition (e.g., a recombinase, an integrase, or a transposase), direct binding of the enzyme to a specific sequence [e.g. TALE repeat variable di-residues (RVD) or gRNA] near a transposase recognition site such that the transposase is prevented from binding to random recognition sites. In some embodiments, an enzyme (e.g., transposase) of the gene transfer system binds to human genomic safe harbor sites (GSHS). TALEs described herein can physically sequester the enzyme to GSHS and promote transposition to nearby TTAA (SEQ ID NO: 1) sequences in close proximity to the RVD TALE nucleotide sequences. GSHSs in open chromatin sites are specifically targeted based on the predilection for transposases to insert into open chromatin. In addition, dCas9 (i.e. deficient for nuclease activity) is programmed with gRNAs directed to bind at a desired sequence of DNA in GSHS.

[0017] In some aspects, a composition is provided that comprises an enzyme capable of transposition comprising (a) a TALE DBD or a dCas9/gRNA DBD; (b) an enzyme capable of targeted genomic integration by transposition, the enzyme being capable of inserting a transposon at a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site in a GSHS sequence in a nucleic acid molecule; and (c) a linker that connects the TALE or Cas/gRNA DBD and the enzyme.

[0018] In some embodiments, the enzyme, e.g., a transposase or a transposase enzyme, is in a dimeric form (e.g. a head to tail dimer). In some embodiments, the enzyme is in a tetrameric form or in another multimeric form. In some embodiments, the enzyme is in a monomeric form.

[0019] In some embodiments, the composition is suitable for causing insertion of the transposon in the GSHS when contacted with a biological cell. The TALE DBD or dCas/gRNA complex can be suitable for directing the transposase enzyme to the GSHS sequence. In embodiments, the composition comprises a dCas/gRNA complex.

[0020] In some embodiments, a composition is provided that comprises an enzyme capable of transposition comprising (a) a dCas9/gRNA complex; (b) an enzyme capable of targeted genomic integration by transposition, the enzyme being capable of inserting a transposon at a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site in a GSHS sequence in a nucleic acid molecule; and (c) a linker that connects the dCas/gRNA complex and the enzyme.

[0021] In embodiments, the GSHS is in an open chromatin location in a chromosome. In some embodiments, the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor, and human Rosa26 locus. In some embodiments, the GSHS is located on human chromosome 2, 4, 6, 10, 11, or 17.

[0022] In some embodiments, the GSHS is selected from sites listed in FIG. 3 and FIG. 4, or a variant thereof (e.g. having about 1, or about 2, or about 3, or about 4, or about 5 mutations, independently selected from an insertion, substitution or deletion). In some embodiments, the TALE DBD comprises a sequence of FIG. 3 or a variant thereof (e.g. having about 1, or about 2, or about 3, or about 4, or about 5 mutations, independently selected from an insertion, substitution or deletion). In some embodiments, the dCas/gRNA DBD comprises a sequence of FIG. 4, or a variant thereof (e.g. having about 1, or about 2, or about 3, or about 4, or about 5 mutations, independently selected from insertion, substitution or deletion).

[0023] In some embodiments, the GSHS is within about 25, or about 50, or about 100, or about 150, or about 200, or about 300, or about 500 nucleotides of the TA dinucleotide site or TTAA (SEQ ID NO: 1) tetranucleotide site. In some embodiments, the GSHS is greater than 500 nucleotides from the TA dinucleotide site or TTAA (SEQ ID NO: 1) tetranucleotide site.

[0024] In embodiments, the TALE DBD comprises one or more repeat sequences. In some embodiments, the TALE DBD or repeat variable di-residue (RVD) comprises about 14, or about 15, or about, 16, or about 17, or about 18, or about 18.5 amino acid repeat sequences. In some embodiments, the RVD is included within TALE amino acid repeat sequences comprising 33 or 34 amino acids.

[0025] In some embodiments, the one or more of the TALE DBD repeat sequences comprise an RVD at residue 12 or 13 of the 33 or 34 amino acids. The RVD can recognize certain base pair(s) or residue(s) of the target DNA. In some embodiments, the RVD recognizes one base pair in the nucleic acid molecule. In some embodiments, the RVD recognizes a "C" residue in the nucleic acid molecule and the RVD is selected from HD, N(gap), HA, ND, and HI. In some embodiments, the RVD recognizes a "G" residue in the nucleic acid molecule and the RVD is selected from NN, NH, NK, HN, and NA. In some embodiments, the RVD recognizes an "A" residue in the nucleic acid molecule and the RVD is selected from NI and NS. In some embodiments, the RVD recognizes a "T" residue in the nucleic acid molecule and the RVD is selected from NG, HG, H(gap), and IG. In embodiments, the enzyme (e.g., without limitation, a transposase enzyme) is capable of inserting a transposon at a TA dinucleotide site. In some embodiments, the enzyme is capable of inserting a transposon at a TTAA (SEQ ID NO: 1) tetranucleotide site.

[0026] In embodiments, a nucleic acid encoding the enzyme capable of targeted genomic integration by transposition comprises an intein. In embodiments, the nucleic acid encodes the enzyme in the form of first and second portions with the intein encoded between the first and second portions, such that the first and second portions are fused into a functional enzyme upon post-translational excision of the intein from the enzyme.

[0027] In embodiments, the enzyme is a recombinase or an integrase. In embodiments, the recombinase is an integrase.

[0028] In embodiments, the integrase is a transposase or the recombinase is a transposase. In embodiments, the transposase has one or more mutations that confer hyperactivity. In embodiments, the transposase is a mammal-derived transposase, optionally encoded by a helper RNA.

[0029] In embodiments, the enzyme is derived from Bombyx mori, Xenopus tropicalis, Trichoplusia ni, or Myotis lucifugus. In embodiments, the enzyme is an engineered version, including but not limited to an enzyme that is a monomer, dimer, tetramer (or another multimer), hyperactive, or has a reduced interaction with non-TTAA (SEQ ID NO: 1) recognitions sites (Int-), derived from Bombyx mori, Xenopus tropicalis, Trichoplusia ni, or Myotis lucifugus. In some embodiments, the transposase enzyme is a Myotis lucifugus transposase (referred to herein as MLT or an MLT transposase), which can be either the wild type, monomer, dimer, tetramer (or another multimer), hyperactive, an Int-mutant, or any other variant.

[0030] In embodiments, a hyperactive form or Int-form of an MLT transposase has one or more mutations selected from L573X, E574X, and S2X, wherein X is any amino acid or no amino acid, optionally X is A, G, or a deletion, optionally the mutations are L573del, E574del, and S2A.

[0031] In embodiments, an MLT transposase, referred to herein as a corrected, engineered MLT transposase, has L573del, E574del, and S2A mutations. Such MLT transposase comprises an amino acid sequence of SEQ ID NO: 2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the MLT transposase is encoded by a nucleotide sequence of SEQ ID NO: 3, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0032] In embodiments, an MLT transposase has the amino acid of SEQ ID NO: 4, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In some embodiments, the MLT transposase is encoded by the nucleotide sequence of SEQ ID NO: 5, or a nucleotide acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0033] In embodiments, a hyperactive, Int-, or other forms of an MLT transposase include a mutation from FIGS. 5A and 5B, e.g. without limitation, about 1, or about 2, or about 3, or about 4, or about 5 mutations. In embodiments, the transposase can include any of the mutations depicted in FIGS. 5A and 5B, or equivalents thereof.

[0034] In embodiments, an MLT transposase in accordance with embodiments of the present disclosure comprises one or more hyperactive mutations that confer hyperactivity upon the MLT transposase. In embodiments, hyperactive mutants comprise one or more substitutions at S8, C13, and N125. In embodiments, hyperactive mutations comprise one or more of S8P, C13R, and N125K mutations.

[0035] In embodiments, an MLT transposase has an amino acid sequence having hyperactive mutations at positions which correspond to at least one of S8P, C13R, and N125K mutations relative to the amino acid sequence of SEQ ID NO: 2. In embodiments, an MLT transposase has an amino acid sequence of SEQ ID NO: 7, which has a mutation at a position which corresponds to hyperactive N125K mutation relative to the amino acid sequence of SEQ ID NO: 2.

[0036] In embodiments, an MLT transposase has an amino acid sequence of SEQ ID NO: 9, which comprises mutations at positions which correspond to hyperactive S8P and C13R mutations relative to the amino acid sequence of SEQ ID NO: 2.

[0037] In embodiments, an MLT transposase has an amino acid sequence having hyperactive mutations at positions which correspond to at least one of S8P, C13R, and N125K mutations relative to the amino acid sequence of SEQ ID NO: 2. It should be appreciated that the MLT transposase having the amino acid sequence of SEQ ID NO: 2 can have two hyperactive mutations (S8P and C13R), without the N125K mutation, or the MLT transposase having the amino acid sequence of SEQ ID NO: 2 can have any other mutation(s) (e.g., any one or more of mutations in FIGS. 5A and 5B). In embodiments, an MLT transposase has an amino acid sequence of SEQ ID NO: 340, which comprises hyperactive mutations at positions which correspond to S8P, C13R, and N125K mutations relative to the amino acid sequence of SEQ ID NO: 2.

[0038] In embodiments, the transposase enzyme is derived from Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Myotis lucifugus, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pteropus vampyrus, Pipistrellus kuhlii, troglodytes, Molossus molossus, or Homo sapiens. In embodiments, the transposase enzyme is derived from any of Trichoplusia ni, Myotis lucifugus, Myotis myotis, Pan troglodytes, or Pteropus vampyrus (see FIG. 7). The transposases can have one or more hyperactive and/or integration deficient mutations selected from FIGS. 5A and 5B, or equivalents thereof. One skilled in the art can correspond such mutants to transposases from any of Trichoplusia ni, Myotis lucifugus, Myotis myotis, or Pteropus vampyrus, with reference to FIG. 7. Also, one skilled in the art can correspond such mutants to transposases from Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Myotis lucifugus, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pteropus vampyrus, Pipistrellus kuhlii, troglodytes, Molossus molossus, or Homo sapiens.

[0039] In some embodiments, the enzyme (e.g., without limitation, a transposase) has a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity to a nucleotide sequence of any of Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pteropus vampyrus, Pipistrellus kuhlii, and Molossus molossus. In some embodiments, the transposase enzyme can have an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of any of Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pteropus vampyrus, Pipistrellus kuhlii, and Molossus molossus.

[0040] In embodiments, the enzyme (e.g., without limitation, a transposase) is an engineered version, including but not limited to a transposase enzyme that is a monomer, dimer, tetramer, hyperactive, or has a reduced interaction with non-TTAA (SEQ ID NO: 1) recognitions sites (Int-), derived from any of Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Myotis lucifugus, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pteropus vampyrus, Pipistrellus kuhlii, Pan troglodytes, Molossus molossus, and Homo sapiens. The transposase enzyme can be either the wild type, monomer, dimer, tetramer or another multimer, hyperactive, or an Int-mutant.

[0041] In some embodiments, the linker that connects the TALE DBD and the enzyme capable of targeted genomic integration by transposition is a flexible linker. In some embodiments, the flexible linker is substantially comprised of glycine and serine residues, optionally wherein the flexible linker comprises (Gly.sub.4Ser).sub.n, where n is from about 1 to about 12. The flexible linker can be of about 20, or about 30, or about 40, or about 50, or about 60 amino acid residues.

[0042] A composition comprising an enzyme capable of transposition in accordance with embodiments of the present disclosure can include one or more non-viral vectors. Also, the enzyme (e.g., a chimeric transposase) can be disposed on the same (cis) or different vector (trans) than a transposon with a transgene. Accordingly, in some embodiments, the chimeric transposase and the transposon encompassing a transgene are in cis configuration such that they are included in the same vector. In some embodiments, the chimeric transposase and the transposon encompassing a transgene are in trans configuration such that they are included in different vectors. The vector is any non-viral vector in accordance with the present disclosure.

[0043] In some aspects, a nucleic acid encoding an enzyme capable of targeted genomic integration by transposition (e.g., a chimeric transposase) in accordance with embodiments of the present disclosure is provided. The nucleic acid can be DNA or RNA. In some embodiments, the nucleic acid encoding the enzyme is DNA. In some embodiments, the nucleic acid encoding the enzyme capable of targeted genomic integration by transposition (e.g., a chimeric transposase) is RNA such as, e.g., helper RNA. In embodiments, the chimeric transposase is incorporated into a vector. In some embodiments, the vector is a non-viral vector.

[0044] In embodiments, a nucleic acid encoding a transposon is a DNA, referred to as a "donor DNA." In embodiments, a nucleic acid encoding an enzyme capable of targeted genomic integration by transposition (e.g., a chimeric transposase) is helper RNA. In embodiments, the donor DNA is incorporated into a plasmid. In embodiments, the donor DNA is a plasmid. In some aspects, a host cell comprising the nucleic acid in accordance with embodiments of the present disclosure is provided.

[0045] In some embodiments, a composition or a nucleic acid in accordance with embodiments of the present disclosure is provided wherein the composition is in the form of a lipid nanoparticle (LNP).

[0046] In embodiments, a nucleic acid encoding the enzyme and a nucleic acid encoding the transposon are contained within the same lipid nanoparticle (LNP). In some embodiments, the nucleic acid encoding the enzyme and the nucleic acid encoding the transposon are a mixture incorporated into or associated with the same LNP. In some embodiments, the nucleic acid encoding the enzyme and the nucleic acid encoding the transposon are in the form of a co-formulation incorporated into or associated with the same LNP.

[0047] In embodiments, the LNP is selected from 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), a cationic cholesterol derivative mixed with dimethylaminoethane-carbamoyl (DC-Chol), phosphatidylcholine (PC), triolein (glyceryl trioleate), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000](DSPE-PEG), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethyleneglycol-2000 (DMG-PEG 2K), and 1,2 distearol-sn-glycerol-3phosphocholine (DSPC) and/or comprising of one or more molecules selected from polyethylenimine (PEI) and poly(lactic-co-glycolic acid) (PLGA), and N-Acetylgalactosamine (GalNAc).

[0048] In some embodiments, an LNP can be as described, e.g. in Patel et al., J Control Release 2019; 303:91-100. The LNP can comprise one or more of a structural lipid (e.g. DSPC), a PEG-conjugated lipid (CDM-PEG), a cationic lipid (MC3), cholesterol, and a targeting ligand (e.g. GalNAc).

[0049] In some aspects, a method for inserting a gene into the genome of a cell is provided that comprises contacting a cell with an enzyme (e.g., without limitation, a chimeric transposase) in accordance with embodiments of the present disclosure. The method can be in vivo or ex vivo method.

[0050] In some embodiments, the cell is contacted with a nucleic acid encoding the enzyme (e.g., without limitation, a chimeric transposase). In some embodiments, the cell is contacted with an RNA encoding the chimeric transposase, and/or with a construct comprising a transposon with flanking insulators such as, e.g. HS4 and D4Z4. In some embodiments, the cell is contacted with a DNA encoding the chimeric transposase.

[0051] In some embodiments, the transposon is flanked by one or more inverted terminal ends. The transposon can be under control of a tissue-specific promoter. In some embodiments, the transposon is an ATP Binding Cassette Subfamily A Member 4 gene (ABC) transporter gene (ABCA4), or functional fragment thereof. As another example, in some embodiments, the transposon is a very low-density lipoprotein receptor gene (VLDLR) or a low-density lipoprotein receptor gene (LDLR), or a functional fragment thereof.

[0052] In embodiments, the enzyme is a transposase such as a chimeric transposase, and the method provides reduced insertional mutagenesis or oncogenesis as compared to a method with a non-chimeric transposase.

[0053] In embodiments, the method is used to treat an inherited or acquired disease in a patient in need thereof.

[0054] For example, in some embodiments, the method is used for treating and/or mitigating a class of Inherited Macular Degeneration (IMDs) (also referred to as Macular dystrophies (MDs), including Stargardt disease (STGD), Best disease, X-linked retinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. The STGD can be STGD Type 1 (STGD1). In some embodiments, the STGD can be STGD Type 3 (STGD3) or STGD Type 4 (STGD4) disease. The IMD can be characterized by one or more mutations in one or more of ABCA4, ELOVL4, PROM1, BEST1, and PRPH2. The gene therapy can be performed using transposon-based vector systems, with the assistance by chimeric transposases in accordance with the present disclosure, which are provided on the same vector as the gene to be transferred (cis) or on a different vector (trans) or as RNA. The transposon can comprise an ATP binding cassette subfamily A member 4 (ABCA4), or functional fragment thereof, and the transposon-based vector systems can operate under the control of a retina-specific promoter.

[0055] In some embodiments, the method is used for treating and/or mitigating familial hypercholesterolemia (FH), such as homozygous FH (HoFH) or heterozygous FH (HeFH) or disorders associated with elevated levels of low-density lipoprotein cholesterol (LDL-C). The gene therapy can be performed using transposon-based vector systems, with the assistance by enzymes (e.g., without limitation, chimeric transposases) in accordance with the present disclosure, which are provided on the same vector (cis) as the gene to be transferred or on a different vector (trans, e.g., a donor DNA/helper RNA system). The transposon can comprise a very low-density lipoprotein receptor gene (VLDLR) or a low-density lipoprotein receptor gene (LDLR), or a functional fragment thereof. The transposon-based vector systems can operate under control of a liver-specific promoter. In some embodiments, the liver-specific promoter is an LP1 promoter. The LP1 promoter can be a human LP1 promoter, which can be constructed as described, e.g., in Nathwani et al. Blood vol. 107(7) (2006):2653-61.

[0056] It should be appreciated that any other inherited or acquired diseases can be treated and/or mitigated using the method in accordance with the present disclosure.

[0057] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

BRIEF DESCRIPTION OF DRAWINGS

[0058] FIGS. 1A-D depict non-limiting representations of chimeric, monomer or head-to-tail dimer transposases that are designed to target human GSHS using TALE and Cas9/guide RNA DNA binders. FIG. 1A. TALEs include nuclear localization signals (NLS) and an activation domain (AD) to function as transcriptional activators. The DNA binding domain has approximately 16.5 repeats of 33-34 amino acids with a residual variable di-residue (RVD) at position 12-13. FIG. 1B. RVDs are shown that have specificity for one or several nucleotides. Only bases of the DNA leading strand are shown. FIG. 1C. A chimeric transposase construct comprising a TALE DNA-binding protein fused thereto by a linker that is greater than 23 amino acids in length (top) and a chimeric transposase construct comprising dCas9 linked to one or more guide RNAs (bottom). FIG. 1D. A schematic diagram showing that chimeric transposases form dimers or tetramers at open chromatin to insert donor DNA at TTAA (SEQ ID NO: 1) recognition sites near DNA binding regions targeted by TALEs or dCas9/gRNA. Binding of the TALE or dCas9/gRNA to GSHS physically sequesters the transposase as a monomer or dimer to the same location and promotes transposition to the nearby TTAA (SEQ ID NO: 1) sequences (FIG. 3 and FIG. 4) near repeat variable di-residues (RVD) nucleotide sequences. All RVDs are preceded by a thymine (T) to bind to the NTR shown in FIG. 1A).

[0059] FIG. 2 is a non-limiting representation of a system in accordance with embodiments of the present disclosure comprising a nucleic acid (e.g., helper RNA) encoding an enzyme capable of targeted genomic integration by transposition and a nucleic acid encoding a transposase (donor DNA). The helper RNA is translated into a bioengineered enzyme (e.g., integrase, recombinase, or transposase) that recognizes specific ends and seamlessly inserts the donor DNA into the human genome in a site-specific manner without a footprint. The enzyme can form a dimer or a tetramer at open chromatin to insert donor DNA at TTAA (SEQ ID NO: 1) recognition sites near DNA binding regions targeted by dCas9/gRNA or TALEs. Binding of the dCas9/gRNA to TALE GSHS physically sequesters the enzyme to the same location and promotes transposition to the nearby TTAA (SEQ ID NO: 1) sequences (see FIG. 3 and FIG. 4).

[0060] FIGS. 3 and 4 depict DNA binding codes for human genomic safe harbor sites in areas of open chromatin (FIG. 3) and guide RNAs to target human genomic safe harbor sites using dCas in areas of open chromatin (FIG. 4). Genomic locations for chromosomes 2, 4, 6, and 11 are adapted from Pellenz et al. (Hum Gene Ther 2019; 30:814-28) and chromosomes 10 and 17 from Papapetrou et al. (Nat Biotechnol 2011; 29:73-8). Sequences were downloaded from the UCSC Genome browser using hg18 or hg19 and evaluated with E-TALEN, a software tool to design and evaluate TALE DBD and WU-CRISPR, a software tool to design guide RNAs.

[0061] FIG. 5A depicts hyperactive MLT mutants.

[0062] FIG. 5B depicts excision positive and integration deficient (Int-) MLT mutants.

[0063] FIG. 6A depicts the three dimensional MLT protein structure with 100% confidence that shows DNA binding domains.

[0064] FIG. 6B depicts secondary structure prediction for an MLT transposase comprising the amino acid sequence of SEQ ID NO: 4 encoded by a nucleotide sequence of SEQ ID NO: 5

[0065] FIG. 7 depicts an amino acid sequence alignment of piggyBac ("Tni") transposase to MLT ("bat") transposase and other bat transposases (Trichoplusia ni, Myotis lucifugus, Myotis myotis, and Pteropus vampyrus). Amino acid sequence alignment of piggyBac (SEQ ID NO: 10) versus MLT and other mammalian transposases (SEQ ID NO: 14 (Myotis lucifugus), SEQ ID NO: 12 (Myotis myotis 2a), SEQ ID NO: 13 (Myotis myotis 1), SEQ ID NO: 11 (Pteropus vampyrus), SEQ ID NO: 14 (Myotis lucifugus 2), SEQ ID NO: 15 (Myotis myotis 2), and SEQ ID NO: 16 (Myotis myotis 2b), appear in the order listed below under "Consensus").

[0066] FIGS. 8A and 8B depict non-limiting examples of construct templates. FIG. 8A depicts a plasmid construct template that transcribes transposase RNA that is later processed with a 5'-m7G cap1 and pseudouridine substitution. FIG. 8B depicts a generic MLT donor DNA construct template for use with any transgene.

[0067] FIG. 9A is a bar chart illustrating integration efficiency of hyperactive piggyBac transposase versus hyperactive MLT variants (S8P/C13R double mutant; L573del E574del) using sequences from Yusa et al. (2010).

[0068] FIG. 9B is a bar chart illustrating integration efficiency of engineered MLT (S8P/C13R double mutant; L573del E574del, S2A) compared to hyperactive piggyBac, using sequences from Yusa et al. (2010).

[0069] FIG. 10 depicts a nucleotide sequence alignment of MLT (human codon-optimized for RNA) and a published sequence by Mitra et al. (Proc Natl Acad Sci USA. 2013 Jan. 2; 110(1):234-9) (Identity 77.67%, Gaps 1.44%).

[0070] FIG. 11 depicts a nucleotide sequence alignment of MLT and a sequence from WO2010085699 (Identity 73.68%, Gaps 1.16%).

[0071] FIG. 12 depicts an amino acid sequence alignment of MLT (L573del/E574del/S2A, with S8P, C13R, and N125K mutations) and published sequence by Mitra et al. (Mitra contained 2 extra amino acids on C-terminus).

[0072] FIG. 13 depicts comparison of an amino acid of an engineered MLT (L573del/E574del/S2A, with S8P and C13R mutations, "MLT") and the sequence from WO2010085699.

[0073] FIG. 14 depicts comparison of a terminal left end of MLT to a published sequence (Ray et al., piggyBac1_ML).

[0074] FIG. 15 depicts comparison of a terminal right end of MLT to a published sequence (Ray et al. piggyBac1_ML).

[0075] FIG. 16 depicts a DNA donor construct template used with either Myotis lucifugus transposase (MLT) or piggyBac (PB) transposase, for an integration assay. The DNA donor construct template has a cytomegalovirus (CMV) promoter that drives expression of green fluorescent protein (GFP).

[0076] FIGS. 17A and 17B show results of functional assessment of the hyperactive MLT transposase mutants in HeLa cell. FIG. 17A shows that mammalian transposon (Ts) variants S8P, C13R, N125K and S8P/C13R have higher excision frequency that the native enzyme. FIG. 17B shows functional transgene expression in HeLa cells transfected with a donor neomycin transgene, 1:20 serial dilutions. The mammalian MLT transposase variant S8P/C13R showed comparable relative integration to the insect piggyBac in HeLa cells.

[0077] FIG. 18 are bar charts illustrating percent (%) of integration efficiency of MLT transposase hyperactive mutants in HEK293 cells, for no MLT, MLT, N125K mutant, and S8P/C13R mutant. The double mutant S8P/C13R shows that highest integration efficiency was observed in HEK293 cells. The MLT transposase is an MLT transposase comprising the amino acid sequence of SEQ ID NO: 4 and encoded by a nucleotide sequence of SEQ ID NO: 5.

[0078] FIGS. 19A and 19B show images of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. FIG. 19A shows analysis of purified MBP-MLT transposase fusion protein by an amylose-resin column. A major protein band of 100+ kDa was identified by SDS-PAGE after purification of the expressed protein (MBP-MLT transposase) from the supernatant of the sonicated bacteria on a column of amylose resin. In FIG. 19B, shows a 67.5 kDa MLT transposase-specific band was shown after overnight cleavage of the MBP tag by TEV protease and heparin elution.

[0079] FIG. 20 shows Superdex size exclusion chromatography of maltose-binding protein (MBP)-MLT transposase fusion protein.

[0080] FIG. 21 depicts an example of a donor plasmid comprising an MLT transposon.

[0081] FIGS. 22A, 22B, 22C, 22B, and 22D are bar charts illustrating integration efficiency and excision activity of variants of a hyperactive form of piggyBac (hypPB) compared to a hyperactive MLT transposase (hypMLT) that comprises L573del/E574del/S2A and has the S8P/C13R mutations (the MLT transposase encoded by the nucleotide sequence of SEQ ID NO: 8 and having the amino acid sequence of SEQ ID NO: 9). FIG. 22A shows % of integration activity for no MLT, MLT-dCas9, MLT-dCas12j, hyperacive piggyBac-dCas12j, hyperacive piggyBac-dCas9, hyperacive piggyBac, and MLT. FIG. 22B shows % of excision activity for no MLT, MLT-Intein-N-terminus, MLT1, and MLT2. FIG. 22C shows % of integration activity for no MLT, MLT-Intein-N-terminus, MLT1, and MLT2. FIG. 22D shows % of excision activity for no MLT, MLT-dCas12j, MLT-dCas9, MLT-Intein-N-terminus dCas9, MLT-Intein-N-terminus, MLT-Intein-N-terminus TALE, MLT-TALE10, and MLT. MLT-TALE10 in 27 bp and 49 bp from TTAA (SEQ ID NO: 1) sites in hROSA29.

[0082] FIGS. 23A, 23B, 23C, 23D, and 23E depict examples of a structure of targeting piggyBac plasmids used in the present study.

[0083] FIG. 23F is a non-limiting schematic of a model for improvement of specificity by disruption of the piggyBac transposase DNA binding domain DBD, in accordance with embodiments of the present invention.

[0084] FIG. 23G depicts an MLT transposase attached to dCas by using e.g. NpuN (Intein-N) (SEQ ID NO: 423) and NpuC (Intein-C) (SEQ ID NO: 424) intein protein splicing. Other dCas can be substituted to target specific genomic sites.

[0085] FIG. 23H depicts a chimeric MLT transposase construct attached to a TALE DNA binder. Other TALEs and transposases can be substituted to target specific genomic sites.

[0086] FIG. 24A depicts positive clonal lines containing targeted insertions to human ROSA26 using hyperactive piggyBac transposase donor and helper with Cas9/gRNA, identified in the present disclosure.

[0087] FIG. 24B depicts a nested PCR strategy to detect the insertion of a donor MLT at a specific TTAA (SEQ ID NO: 1) site in human ROSA26 locus using MLT helper with Cas9 and two different sets of gRNA (Set 1: AATCGAGAAGCGACTCGACA (SEQ ID NO: 425), TGCCCTGCAGGGGAGTGAGC (SEQ ID NO: 426); Set 2: GAAGCGACTCGACATGGAGG (SEQ ID NO: 427), CCTGCAGGGGAGTGAGCAGC (SEQ ID NO: 428)) that were 61 bp and 62 bp respectively, from the TTAA (SEQ ID NO: 1) targeted site.

[0088] FIG. 24C depicts a 1.0% agarose gel showing the expected nester PCR fragment when an MLT donor is inserted at hROSA26 after transfection with MLT helper with Cas9/gRNA, identified in the present disclosure.

[0089] FIG. 24D depicts a DNA sequencing chromatogram that shows the correct junction DNA sequence when a MLT donor is inserted at hROSA26 after transfection with an MLT helper with Cas9/gRNA, identified in the present disclosure.

[0090] FIG. 25 shows initial Huh7 cell lines transfected under different conditions to show that Huh7 express GFP. The rows show (from the top) untreated cells, mock, cells treated with MLT, and cells treated with pmaxGFP; the columns show controls at day 1 (D1), day 3 (D3), and day 7 (D7).

[0091] FIG. 26 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only, at different ratios, 24 hours post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0092] FIG. 27 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only at different ratios, 72 hours post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0093] FIG. 28 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only at different ratios, 1 week post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0094] FIGS. 29A and 29B show the viability of HEK293 cells after nucleofection in 96-well plates, lipofection in T25 flasks, and lipofection in 96-well plates, 14 days after transfection (FIG. 29A) and 21 days after transfection (FIG. 29B). Cell viability is slightly better in 96-well plates at 14 days and 21 days after transfection. There are no significant differences in cell viability between the untreated cells and treated cells.

[0095] FIGS. 29C and 29D show the percentage of GFP/mCherry positive HEK293 cells after nucleofection in 96-well plates, lipofection in T25 flasks, and lipofection in 96-well plates, 14 days after transfection (FIG. 29C) and 21 days after transfection (FIG. 29D). A FACs gating strategy was applied to samples within each experiment. Selection of GFP-positive and mCherry-positive cell population was obtained. mCherry RNA expression was undetectable at Day 14. The highest % GFP positive cells was observed in the lipofectamine T25 format. The integration efficiency was 35% at 14 days, and 37% at 21 days.

[0096] FIG. 29E shows the percentage of GFP positive HEK293 cells after nucleofection lipofection in T25 flasks. The % GFP positive cells was the same in CMV-GFP MLT Donor alone compared to CMV-GFP MLT Donor plus MLT Helper RNA. The % GFP positivity declined rapidly in HEK293 cells transfected with CMV-GFP MLT Donor alone and reached 5% at Day 21. The % GFP positivity stabilized in HEK293 cells transfected with CMV-GFP MLT Donor plus MLT Helper RNA and reached 42% at Day 21. The integration efficiency was calculated at 37%. The top curve is "CMV-GFP Donor".

[0097] FIGS. 30A, 30B, 30C, and 30D show the FACS gating strategy that determined that neither RNA or DNA affected the viability of HEK293 cells (FIGS. 29A and 29B), RNA expression decreased rapidly after transfection and was undetectable by Day 14 (FIGS. 29C and 29D), and the DNA MLT Donor/MLT RNA Helper system has a high integration efficiency (FIG. 29E). FIG. 30A shows all cells, FIG. 30B shows single cells, and FIG. 30C shows live cells. FIG. 30D shows GFP single-positive cells, mCherry single-positive cells, double-positive cells, and double-negative cells.

[0098] FIG. 31 shows transfection of CMV-GFP MLT Donor plus MLT Helper DNA 24 hours post transfection of HT1080 cells. The results at 24 hours are similar to the DNA MLT Donor/MLT RNA Helper system.

[0099] FIG. 32 shows transfection of CMV-GFP MLT Donor plus MLT Helper DNA 2 weeks post transfection of HT1080 cells. The results suggest that DNA MLT Donor/MLT DNA Helper system (.about.20% GFP+ cells) has less integration efficiency compared to DNA MLT Donor/MLT DNA Helper system.

DETAILED DESCRIPTION OF THE INVENTION

[0100] The present invention is based, in part, on the discovery of an engineered transposase enzyme capable of gene insertion that finds use, e.g., in therapy. In aspects, there is provided an engineered MLT enzyme (occasionally referred to as "engineered", "corrected," "the present MLT", "MLT1" or "MLT2").

[0101] The present invention is based, in part, on the discovery that an enzyme capable of targeted genomic integration by transposition (e.g., a recombinase, an integrase, or a transposase enzyme), as a monomer or a dimer, can be fused with a transcription activator-like effector proteins (TALE) DNA binding domain (DBD) or a dCas9/gRNA to thereby create a chimeric enzyme capable of a site- or locus-specific transposition. The enzyme (e.g., without limitation, a chimeric transposase) utilizes the specificity of TALE DBD to certain sites within a host genome, which allows using DBDs to target any desired location in the genome. In this way, the chimeric transposase in accordance with the present disclosure allows achieving targeted integration of a transgene.

[0102] In embodiments, the enzyme capable of targeted genomic integration by transposition is a recombinase or an integrase. In embodiments, the recombinase is an integrase. In embodiments, the integrase is a transposase or the recombinase is a transposase.

[0103] In embodiments, the transposase has one or more mutations that confer hyperactivity. In embodiments, the transposase is a mammal-derived transposase, optionally a helper RNA transposase. Thus, the present compositions and methods for gene transfer utilize a dual transposon/transposase system. Transposable elements are non-viral gene delivery vehicles found ubiquitously in nature. Transposon-based vectors have the capacity of stable genomic integration and long-lasting expression of transgene constructs in cells. Generally speaking, dual transposon and transposase systems work via a cut-and-paste mechanism whereby transposon DNA containing a transgene(s) of interest is integrated into chromosomal DNA by a transposase enzyme at a repetitive sequence site. Dual transposon/transposase (or "donor/helper") plasmid systems insert a transgene flanked by inverted terminal ends ("ends"), such as TTAA (SEQ ID NO: 1) tetranucleotide sites, without leaving a DNA footprint in the human genome. The transposase enzyme is transiently expressed (on the same or a different vector from a vector encoding the transposon) and it catalyzes the insertion events from the donor plasmid to the host genome. Genomic insertions primarily target introns but may target other TTAA (SEQ ID NO: 1) sites and integrate into approximately 50% of human genes.

[0104] Selection of a transposon system for gene therapy depends on the system's integration site preference. For example, piggyBac (PB) transposon has preference for transcription units, with insertions primarily targeting introns. Some transposases require certain sites in the host DNA for catalytic activity even if the DNA-enzyme complex is brought into the vicinity of the host-DNA. For example, Tcl/mariner transposon integrates into a TA dinucleotide (Fischer et al., Proc Natl Acad Sci USA 2001; 98:6759-64), and piggyBac (PB) transposon integrates into a TTAA (SEQ ID NO: 1) tetranucleotide (Mitra et al., EMBO J 2008; 27:1097-109). A benefit of using transposase-based genomic targeting over nuclease-based techniques is that integration via the cut-and-paste mechanism is readily identified by assaying the copy number of transposon insertions (e.g. (nr)LAM-PCR). Therefore, a single insertion clone is not expected to have additional DNA modifications. In comparison, targetable nucleases are capable of mutating genome without introducing an identifiable insert. Therefore, it may be challenging to confirm the DNA integrity of modified cells. Genomic screens to identify off-target nuclease mutations are complex and limited in sequence coverage.

[0105] As discussed above, viral (e.g. AAV, lentivirus, etc.) and nuclease-based (e.g. CRISPR/Cas, prime editing base editing) gene therapies are typically limited by mutagenesis risk, and also have drawbacks such as immunogenicity, manufacturing costs, cargo size, and reversibility. Transposons are less likely to activate a proto-oncogene than lentivirus or other retroviruses but cause insertional mutagenesis when a transgene is inserted in one or more locations in a host genome other than the intended locations. In particular, the genomic sites recognized by transposases, such as a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site, can be found in multiple locations in a genome such that a transgene can be inserted in unintended locations within the genome and have disruptive, often severe effects on the host. For example, the insertional mutagenesis can affect a function of a metabolic gene. Accordingly, to improve the function of a dual transposon/transposase system as a safe and efficient gene therapy tool, it is desired to increase and control the specificity of a transposase's binding and insertion.

[0106] Accordingly, in some aspects, a composition is provided that comprises an enzyme capable of transposition, comprising (a) a TALE DBD or a dCas9/gRNA complex; (b) an enzyme capable of targeted genomic integration by transposition, the enzyme being capable of inserting a transposon at a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site in a GSHS in a nucleic acid molecule; and (c) a linker that connects the TALE DBD or the dCas9/gRNA complex and the enzyme. In embodiments, the enzyme (e.g., a transposase enzyme) is a head to tail dimer. In some embodiments, the enzyme is a tetramer. In some embodiments, the enzyme is a monomer.

[0107] In embodiments, TALE or dCas9/gRNA DBDs cause the enzyme capable of transposition (e.g., without limitation, a chimeric transposase) to bind specifically to human GSHS. In embodiments, the TALEs or dCas9/gRNA DBD sequester the transposase to GSHS and promote transposition to nearby TA dinucleotide or TTAA (SEQ ID NO: 1) tetranucleotide sites which can be located in proximity to the repeat variable di-residues (RVD) TALE or gRNA nucleotide sequences. The GSHS regions are located in open chromatin sites that are susceptible to transposase activity. Accordingly, the transposase does not only operate based on its ability to recognize TA or TTAA (SEQ ID NO: 1) sites, but it also directs a transposon (having a transgene) to specific locations in proximity to a TALE or dCas9/gRNA DBD. The chimeric transposase in accordance with embodiments of the present disclosure has negligible risk of genotoxicity and exhibits superior features as compared to existing gene therapies.

[0108] In embodiments, the gRNA, e.g. to be associated with dCas9 is AATCGAGAAGCGACTCGACA (SEQ ID NO: 425) and/or TGCCCTGCAGGGGAGTGAGC (SEQ ID NO: 426). In embodiments, the gRNA, e.g. to be associated with dCas9 is GAAGCGACTCGACATGGAGG (SEQ ID NO: 427) and/or CCTGCAGGGGAGTGAGCAGC (SEQ ID NO: 428).

[0109] In some embodiments, a chimeric transposase is mutated to be characterized by reduced or inhibited binding of off-target sequences and consequently reliant on a DBD fused thereto, such as a TALE or dCas9/gRNA DBD, for transposition.

[0110] The described compositions and methods allow reducing random vector and transgene insertion, which increase a mutagenic risk. The described compositions and methods make use of a transposome system that reduces genotoxicity compared to viral- and nuclease-mediated gene therapies. The dual system is designed to avoid the persistence of an active transposase and efficiently transfect human cell lines without significant cytotoxicity.

[0111] In some embodiments, the composition is suitable for causing insertion of the transposon in the GSHS when contacted with a cell comprising a GSHS.

[0112] In some embodiments, the TALE or dCas9/gRNA DBD can be suitable for directing the transposase enzyme to the GSHS sequence.

[0113] In embodiments, TALE or dCas9/gRNA DBDs are customizable, such as a TALE or dCas9/gRNA DBD can be selected for targeting a specific genomic location. In some embodiments, the genomic location is in proximity to a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site.

[0114] In embodiments, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) associated protein 9 (Cas9), or a variant thereof, targets the enzyme to a locus of interest. Cas9 is a generic nuclease, and a guide RNA (gRNA) confers sequence specificity on Cas9 by carrying an identical complementary sequence to a genomic region of interest. Jinek et al. (2012) Science 337:816-821. A CRISPR/Cas9 tool only requires Cas9 nuclease for DNA cleavage and a single-guide RNA (sgRNA) for target specificity. See Jinek et al. (2012); Chylinski et al. (2014) Nucleic Acids Res 42, 6091-6105. The inactivated form of Cas9, which is a nuclease-deficient (or inactive, or "catalytically dead") Cas9, is typically denoted as "dCas9" and has no substantial nuclease activity. Qi, L. S. et al. (2013). Cell 152, 1173-1183. CRISPR/dCas9 binds precisely to specific genomic sequences through targeting of guide RNA (gRNA) sequences. See Dominguez et al., Nat Rev Mol Cell Biol. 2016; 17:5-15; Wang et al., Annu Rev Biochem. 2016; 85:227-64. dCas9 is utilized to edit gene expression when applied to the transcription binding site of a desired site and/or locus in a genome. When the dCas9 protein is coupled to guide RNA (gRNA) to create dCas9 guide RNA complex, dCas9 prevents the proliferation of repeating codons and DNA sequences that might be harmful to an organism's genome. Essentially, when multiple repeat codons are produced, it elicits a response, or recruits an abundance of dCas9 to combat the overproduction of those codons and results in the shut-down of transcription. Thus, dCas9 works synergistically with gRNA and directly affects the DNA polymerase II from continuing transcription.

[0115] In embodiments, the gene-editing system comprises a nuclease-deficient Cas enzyme guide RNA complex. In some embodiments, the gene-editing system comprises a nuclease-deficient (or inactive, or "catalytically dead" Cas9, typically denoted as "dCas9") guide RNA complex.

[0116] In embodiments, the dCas9/gRNA complex comprises a guide RNA selected from: GTTTAGCTCACCCGTGAGCC (SEQ ID NO: 91), CCCAATATTATTGTTCTCTG (SEQ ID NO: 92), GGGGTGGGATAGGGGATACG (SEQ ID NO: 93), GGATCCCCCTCTACATTTAA (SEQ ID NO: 94), GTGATCTTGTACAAATCATT (SEQ ID NO: 95), CTACACAGAATCTGTTAGAA (SEQ ID NO: 96), TAAGCTAGAGAATAGATCTC (SEQ ID NO: 97), and TCAATACACTTAATGATTTA (SEQ ID NO: 98), wherein the guide RNA directs the enzyme to a chemokine (C-C motif) receptor 5 (CCR5) gene.

[0117] In embodiments, the dCas9/gRNA complex comprises a guide RNA selected from:

TABLE-US-00001 See FIG. 4. (SEQ ID NO: 99) CACCGGGAGCCACGAAAACAGATCC; (SEQ ID NO: 100) CACCGCGAAAACAGATCCAGGGACA; (SEQ ID NO: 101) CACCGAGATCCAGGGACACGGTGCT; (SEQ ID NO: 102) CACCGGACACGGTGCTAGGACAGTG; (SEQ ID NO: 103) CACCGGAAAATGACCCAACAGCCTC; (SEQ ID NO: 104) CACCGGCCTGGCCGGCCTGACCACT; (SEQ ID NO: 105) CACCGCTGAGCACTGAAGGCCTGGC; (SEQ ID NO: 106) CACCGTGGTTTCCACTGAGCACTGA; (SEQ ID NO: 107) CACCGGATAGCCAGGAGTCCTTTCG; (SEQ ID NO: 108) CACCGGCGCTTCCAGTGCTCAGACT; (SEQ ID NO: 109) CACCGCAGTGCTCAGACTAGGGAAG; (SEQ ID NO: 110) CACCGGCCCCTCCTCCTTCAGAGCC; (SEQ ID NO: 111) CACCGTCCTTCAGAGCCAGGAGTCC; (SEQ ID NO: 112) CACCGTGGTTTCCGAGCTTGACCCT; (SEQ ID NO: 113) CACCGCTGCAGAGTATCTGCTGGGG; (SEQ ID NO: 114) CACCGCGTTCCTGCAGAGTATCTGC; (SEQ ID NO: 115) AAACGGATCTGTTTTCGTGGCTCCC; (SEQ ID NO: 116) AAACTGTCCCTGGATCTGTTTTCGC; (SEQ ID NO: 117) AAACAGCACCGTGTCCCTGGATCTC; (SEQ ID NO: 118) AAACCACTGTCCTAGCACCGTGTCC; (SEQ ID NO: 119) AAACGAGGCTGTTGGGTCATTTTCC; (SEQ ID NO: 120) AAACAGTGGTCAGGCCGGCCAGGCC; (SEQ ID NO: 121) AAACGCCAGGCCTTCAGTGCTCAGC; (SEQ ID NO: 122) AAACTCAGTGCTCAGTGGAAACCAC; (SEQ ID NO: 123) AAACCGAAAGGACTCCTGGCTATCC; (SEQ ID NO: 124) AAACAGTCTGAGCACTGGAAGCGCC; (SEQ ID NO: 125) AAACCTTCCCTAGTCTGAGCACTGC; (SEQ ID NO: 126) AAACGGCTCTGAAGGAGGAGGGGCC; (SEQ ID NO: 127) AAACGGACTCCTGGCTCTGAAGGAC; (SEQ ID NO: 128) AAACAGGGTCAAGCTCGGAAACCAC; (SEQ ID NO: 129) AAACCCCCAGCAGATACTCTGCAGC; (SEQ ID NO: 130) AAACGCAGATACTCTGCAGGAACGC; (SEQ ID NO: 131) TCCCCTCCCAGAAAGACCTG; (SEQ ID NO: 132) TGGGCTCCAAGCAATCCTGG; (SEQ ID NO: 133) GTGGCTCAGGAGGTACCTGG; (SEQ ID NO: 134) GAGCCACGAAAACAGATCCA; (SEQ ID NO: 135) AAGTGAACGGGGAAGGGAGG; (SEQ ID NO: 136) GACAAAAGCCGAAGTCCAGG; (SEQ ID NO: 137) GTGGTTGATAAACCCACGTG; (SEQ ID NO: 138) TGGGAACAGCCACAGCAGGG; (SEQ ID NO: 139) GCAGGGGAACGGGGATGCAG; (SEQ ID NO: 140) GAGATGGTGGACGAGGAAGG; (SEQ ID NO: 141) GAGATGGCTCCAGGAAATGG; (SEQ ID NO: 142) TAAGGAATCTGCCTAACAGG; (SEQ ID NO: 143) TCAGGAGACTAGGAAGGAGG; (SEQ ID NO: 144) TATAAGGTGGTCCCAGCTCG; (SEQ ID NO: 145) CTGGAAGATGCCATGACAGG; (SEQ ID NO: 146) GCACAGACTAGAGAGGTAAG; (SEQ ID NO: 147) ACAGACTAGAGAGGTAAGGG; (SEQ ID NO: 148) GAGAGGTGACCCGAATCCAC; (SEQ ID NO: 149) GCACAGGCCCCAGAAGGAGA; (SEQ ID NO: 150) CCGGAGAGGACCCAGACACG; (SEQ ID NO: 151) GAGAGGACCCAGACACGGGG; (SEQ ID NO: 152) GCAACACAGCAGAGAGCAAG; (SEQ ID NO: 153) GAAGAGGGAGTGGAGGAAGA; (SEQ ID NO: 154) AAGACGGAACCTGAAGGAGG; (SEQ ID NO: 155) AGAAAGCGGCACAGGCCCAG; (SEQ ID NO: 156) GGGAAACAGTGGGCCAGAGG; (SEQ ID NO: 157) GTCCGGACTCAGGAGAGAGA; (SEQ ID NO: 158) GGCACAGCAAGGGCACTCGG; (SEQ ID NO: 159) GAAGAGGGGAAGTCGAGGGA; (SEQ ID NO: 160) GGGAATGGTAAGGAGGCCTG; (SEQ ID NO: 161) GCAGAGTGGTCAGCACAGAG; (SEQ ID NO: 162) GCACAGAGTGGCTAAGCCCA; (SEQ ID NO: 163) GACGGGGTGTCAGCATAGGG; (SEQ ID NO: 164) GCCCAGGGCCAGGAACGACG; (SEQ ID NO: 165) GGTGGAGTCCAGCACGGCGC; (SEQ ID NO: 166) ACAGGCCGCCAGGAACTCGG; (SEQ ID NO: 167) ACTAGGAAGTGTGTAGCACC; (SEQ ID NO: 168) ATGAATAGCAGACTGCCCCG; (SEQ ID NO: 169) ACACCCCTAAAAGCACAGTG; (SEQ ID NO: 170) CAAGGAGTTCCAGCAGGTGG; (SEQ ID NO: 171) AAGGAGTTCCAGCAGGTGGG; (SEQ ID NO: 172) TGGAAAGAGGAGGGAAGAGG; (SEQ ID NO: 173) TCGAATTCCTAACTGCCCCG; (SEQ ID NO: 174) GACCTGCCCAGCACACCCTG; (SEQ ID NO: 175) GGAGCAGCTGCGGCAGTGGG; (SEQ ID NO: 176) GGGAGGGAGAGCTTGGCAGG; (SEQ ID NO: 177) GTTACGTGGCCAAGAAGCAG; (SEQ ID NO: 178) GCTGAACAGAGAAGAGCTGG; (SEQ ID NO: 179) TCTGAGGGTGGAGGGACTGG; (SEQ ID NO: 180) GGAGAGGTGAGGGACTTGGG; (SEQ ID NO: 181) GTGAACCAGGCAGACAACGA;

(SEQ ID NO: 182) CAGGTACCTCCTGAGCCACG; (SEQ ID NO: 183) GGGGGAGTAGGGGCATGCAG; (SEQ ID NO: 184) GCAAATGGCCAGCAAGGGTG; (SEQ ID NO: 309) CAAATGGCCAGCAAGGGTGG; (SEQ ID NO: 310) GCAGAACCTGAGGATATGGA; (SEQ ID NO: 311) AATACACAGAATGAAAATAG; (SEQ ID NO: 312) CTGGTGACTAGAATAGGCAG; (SEQ ID NO: 313) TGGTGACTAGAATAGGCAGT; (SEQ ID NO: 314) TAAAAGAATGTGAAAAGATG; (SEQ ID NO: 315) TCAGGAGTTCAAGACCACCC; (SEQ ID NO: 316) TGTAGTCCCAGTTATGCAGG; (SEQ ID NO: 317) GGGTTCACACCACAAATGCA; (SEQ ID NO: 318) GGCAAATGGCCAGCAAGGGT; (SEQ ID NO: 319) AGAAACCAATCCCAAAGCAA; (SEQ ID NO: 320) GCCAAGGACACCAAAACCCA; (SEQ ID NO: 321) AGTGGTGATAAGGCAACAGT; (SEQ ID NO: 322) CCTGAGACAGAAGTATTAAG; (SEQ ID NO: 323) AAGGTCACACAATGAATAGG; (SEQ ID NO: 324) CACCATACTAGGGAAGAAGA; (SEQ ID NO: 327) CAATACCCTGCCCTTAGTGG; (SEQ ID NO: 325) AATACCCTGCCCTTAGTGGG; (SEQ ID NO: 326) TTAGTGGGGGGTGGAGTGGG; (SEQ ID NO: 328) GTGGGGGGTGGAGTGGGGGG; (SEQ ID NO: 329) GGGGGGTGGAGTGGGGGGTG; (SEQ ID NO: 330) GGGGTGGAGTGGGGGGTGGG; (SEQ ID NO: 331) GGGTGGAGTGGGGGGTGGGG; (SEQ ID NO: 332) GGGGGTGGGGAAAGACATCG; (SEQ ID NO: 333) GCAGCTGTGAATTCTGATAG; (SEQ ID NO: 334) GAGATCAGAGAAACCAGATG; (SEQ ID NO: 335) TCTATACTGATTGCAGCCAG; (SEQ ID NO: 185) CACCGAATCGAGAAGCGACTCGACA; (SEQ ID NO: 186) CACCGGTCCCTGGGCGTTGCCCTGC; (SEQ ID NO: 187) CACCGCCCTGGGCGTTGCCCTGCAG; (SEQ ID NO: 188) CACCGCCGTGGGAAGATAAACTAAT; (SEQ ID NO: 189) CACCGTCCCCTGCAGGGCAACGCCC; (SEQ ID NO: 190) CACCGGTCGAGTCGCTTCTCGATTA; (SEQ ID NO: 191) CACCGCTGCTGCCTCCCGTCTTGTA; (SEQ ID NO: 192) CACCGGAGTGCCGCAATACCTTTAT; (SEQ ID NO: 193) CACCGACACTTTGGTGGTGCAGCAA; (SEQ ID NO: 194) CACCGTCTCAAATGGTATAAAACTC; (SEQ ID NO: 195) CACCGAATCCCGCCCATAATCGAGA; (SEQ ID NO: 196) CACCGTCCCGCCCATAATCGAGAAG; (SEQ ID NO: 197) CACCGCCCATAATCGAGAAGCGACT; (SEQ ID NO: 198) CACCGGAGAAGCGACTCGACATGGA; (SEQ ID NO: 199) CACCGGAAGCGACTCGACATGGAGG; (SEQ ID NO: 200) CACCGGCGACTCGACATGGAGGCGA; (SEQ ID NO: 201) AAACTGTCGAGTCGCTTCTCGATTC; (SEQ ID NO: 202) AAACGCAGGGCAACGCCCAGGGACC; (SEQ ID NO: 203) AAACCTGCAGGGCAACGCCCAGGGC; (SEQ ID NO: 204) AAACATTAGTTTATCTTCCCACGGC; (SEQ ID NO: 205) AAACGGGCGTTGCCCTGCAGGGGAC; (SEQ ID NO: 206) AAACTAATCGAGAAGCGACTCGACC; (SEQ ID NO: 207) AAACTACAAGACGGGAGGCAGCAGC; (SEQ ID NO: 208) AAACATAAAGGTATTGCGGCACTCC; (SEQ ID NO: 209) AAACTTGCTGCACCACCAAAGTGTC; (SEQ ID NO: 210) AAACGAGTTTTATACCATTTGAGAC; (SEQ ID NO: 211) AAACTCTCGATTATGGGCGGGATTC; (SEQ ID NO: 212) AAACCTTCTCGATTATGGGCGGGAC; (SEQ ID NO: 213) AAACAGTCGCTTCTCGATTATGGGC; (SEQ ID NO: 214) AAACTCCATGTCGAGTCGCTTCTCC; (SEQ ID NO: 215) AAACCCTCCATGTCGAGTCGCTTCC; (SEQ ID NO: 216) AAACTCGCCTCCATGTCGAGTCGCC; (SEQ ID NO: 217) CACCGACAGGGTTAATGTGAAGTCC; (SEQ ID NO: 218) CACCGTCCCCCTCTACATTTAAAGT; (SEQ ID NO: 219) CACCGCATTTAAAGTTGGTTTAAGT; (SEQ ID NO: 220) CACCGTTAGAAAATATAAAGAATAA; (SEQ ID NO: 221) CACCGTAAATGCTTACTGGTTTGAA; (SEQ ID NO: 222) CACCGTCCTGGGTCCAGAAAAAGAT; (SEQ ID NO: 223) CACCGTTGGGTGGTGAGCATCTGTG; (SEQ ID NO: 224) CACCGCGGGGAGAGTGGAGAAAAAG; (SEQ ID NO: 225) CACCGGTTAAAACTCTTTAGACAAC; (SEQ ID NO: 226) CACCGGAAAATCCCCACTAAGATCC; (SEQ ID NO: 227) AAACGGACTTCACATTAACCCTGTC; (SEQ ID NO: 228) AAACACTTTAAATGTAGAGGGGGAC; (SEQ ID NO: 229) AAACACTTAAACCAACTTTAAATGC; (SEQ ID NO: 230) AAACTTATTCTTTATATTTTCTAAC; (SEQ ID NO: 231) AAACTTCAAACCAGTAAGCATTTAC; (SEQ ID NO: 232) AAACATCTTTTTCTGGACCCAGGAC; (SEQ ID NO: 233) AAACCACAGATGCTCACCACCCAAC; (SEQ ID NO: 234) AAACCTTTTTCTCCACTCTCCCCGC; (SEQ ID NO: 235) AAACGTTGTCTAAAGAGTTTTAACC; (SEQ ID NO: 236) AAACGGATCTTAGTGGGGATTTTCC; (SEQ ID NO: 237) AGTAGCAGTAATGAAGCTGG; (SEQ ID NO: 238) ATACCCAGACGAGAAAGCTG;

(SEQ ID NO: 239) TACCCAGACGAGAAAGCTGA; (SEQ ID NO: 240) GGTGGTGAGCATCTGTGTGG; (SEQ ID NO: 241) AAATGAGAAGAAGAGGCACA; (SEQ ID NO: 242) CTTGTGGCCTGGGAGAGCTG; (SEQ ID NO: 243) GCTGTAGAAGGAGACAGAGC; (SEQ ID NO: 244) GAGCTGGTTGGGAAGACATG; (SEQ ID NO: 245) CTGGTTGGGAAGACATGGGG; (SEQ ID NO: 246) CGTGAGGATGGGAAGGAGGG; (SEQ ID NO: 247) ATGCAGAGTCAGCAGAACTG; (SEQ ID NO: 248) AAGACATCAAGCACAGAAGG; (SEQ ID NO: 249) TCAAGCACAGAAGGAGGAGG; (SEQ ID NO: 250) AACCGTCAATAGGCAAAGGG; (SEQ ID NO: 251) CCGTATTTCAGACTGAATGG; (SEQ ID NO: 252) GAGAGGACAGGTGCTACAGG; (SEQ ID NO: 253) AACCAAGGAAGGGCAGGAGG; (SEQ ID NO: 254) GACCTCTGGGTGGAGACAGA; (SEQ ID NO: 255) CAGATGACCATGACAAGCAG; (SEQ ID NO: 256) AACACCAGTGAGTAGAGCGG; (SEQ ID NO: 257) AGGACCTTGAAGCACAGAGA; (SEQ ID NO: 258) TACAGAGGCAGACTAACCCA; (SEQ ID NO: 259) ACAGAGGCAGACTAACCCAG; (SEQ ID NO: 260) TAAATGACGTGCTAGACCTG; (SEQ ID NO: 261) AGTAACCACTCAGGACAGGG; (SEQ ID NO: 262) ACCACAAAACAGAAACACCA; (SEQ ID NO: 263) GTTTGAAGACAAGCCTGAGG; (SEQ ID NO: 264) GCTGAACCCCAAAAGACAGG; (SEQ ID NO: 265) GCAGCTGAGACACACACCAG; (SEQ ID NO: 266) AGGACACCCCAAAGAAGCTG; (SEQ ID NO: 267) GGACACCCCAAAGAAGCTGA; (SEQ ID NO: 268) CCAGTGCAATGGACAGAAGA; (SEQ ID NO: 269) AGAAGAGGGAGCCTGCAAGT; (SEQ ID NO: 270) GTGTTTGGGCCCTAGAGCGA; (SEQ ID NO: 271) CATGTGCCTGGTGCAATGCA; (SEQ ID NO: 272) TACAAAGAGGAAGATAAGTG; (SEQ ID NO: 273) GTCACAGAATACACCACTAG; (SEQ ID NO: 274) GGGTTACCCTGGACATGGAA; (SEQ ID NO: 275) CATGGAAGGGTATTCACTCG; (SEQ ID NO: 276) AGAGTGGCCTAGACAGGCTG; (SEQ ID NO: 277) CATGCTGGACAGCTCGGCAG; (SEQ ID NO: 278) AGTGAAAGAAGAGAAAATTC; (SEQ ID NO: 279) TGGTAAGTCTAAGAAACCTA; (SEQ ID NO: 280) CCCACAGCCTAACCACCCTA; (SEQ ID NO: 281) AATATTTCAAAGCCCTAGGG; (SEQ ID NO: 282) GCACTCGGAACAGGGTCTGG; (SEQ ID NO: 283) AGATAGGAGCTCCAACAGTG; (SEQ ID NO: 284) AAGTTAGAGCAGCCAGGAAA; (SEQ ID NO: 285) TAGAGCAGCCAGGAAAGGGA; (SEQ ID NO: 286) TGAATACCCTTCCATGTCCA; (SEQ ID NO: 287) CCTGCATTGCACCAGGCACA; (SEQ ID NO: 288) TCTAGGGCCCAAACACACCT; (SEQ ID NO: 289) TCCCTCCATCTATCAAAAGG; (SEQ ID NO: 290) AGCCCTGAGACAGAAGCAGG; (SEQ ID NO: 291) GCCCTGAGACAGAAGCAGGT; (SEQ ID NO: 292) AGGAGATGCAGTGATACGCA; (SEQ ID NO: 293) ACAATACCAAGGGTATCCGG; (SEQ ID NO: 294) TGATAAAGAAAACAAAGTGA; (SEQ ID NO: 295) AAAGAAAACAAAGTGAGGGA; (SEQ ID NO: 296) GTGGCAAGTGGAGAAATTGA; (SEQ ID NO: 297) CAAGTGGAGAAATTGAGGGA; (SEQ ID NO: 298) GTGGTGATGATTGCAGCTGG; (SEQ ID NO: 299) CTATGTGCCTGACACACAGG; (SEQ ID NO: 300) GGGTTGGACCAGGAAAGAGG; (SEQ ID NO: 301) GATGCCTGGAAAAGGAAAGA; (SEQ ID NO: 302) TAGTATGCACCTGCAAGAGG; (SEQ ID NO: 303) TATGCACCTGCAAGAGGCGG; (SEQ ID NO: 304) AGGGGAAGAAGAGAAGCAGA; (SEQ ID NO: 305) GCTGAATCAAGAGACAAGCG; (SEQ ID NO: 306) AAGCAAATAAATCTCCTGGG; (SEQ ID NO: 307) AGATGAGTGCTAGAGACTGG; and (SEQ ID NO: 308) CTGATGGTTGAGCACAGCAG.

[0118] Embodiments of the present disclosure make use of the ability of TALE or dCas9/gRNA DBDs to target specific sites in a host genome. The DNA targeting ability of a TALE or dCas9/gRNA DBD is provided by TALE repeat sequences (e.g., modular arrays) or gRNA which are linked together to recognize flanking DNA sequences. Each TALE or gRNA can recognize certain base pair(s) or residue(s).

[0119] TALE nucleases (TALENs) are a known tool for genome editing and introducing targeted double-stranded breaks. TALENs comprise endonucleases, such as Fokl nuclease domain, fused to a customizable DBD. This DBD is composed of highly conserved repeats derived from TALEs, which are proteins secreted by Xanthomonas bacteria to alter transcription of genes in host plant cells. The DBD includes a repeated highly conserved 33-34 amino acid sequence with divergent 12th and 13th amino acids. These two positions, referred to as the RVD, are highly variable and show a strong correlation with specific base pair or nucleotide recognition. This straightforward relationship between amino acid sequence and DNA recognition has allowed for the engineering of specific DBDs by selecting a combination of repeat segments containing the appropriate RVDs. Boch et al. Nature Biotechnology. 2011; 29 (2): 135-6.

[0120] Accordingly, TALENs can be readily designed using a "protein-DNA code" that relates modular DNA-binding TALE repeat domains to individual bases in a target-binding site. See Joung et al. Nat Rev Mol Cell Biol. 2013; 14(1):49-55. doi:10.1038/nrm3486. FIG. 3, for example, shows such code.

[0121] It has been demonstrated that TALENs can be used to target essentially any DNA sequence of interest in human cell. Miller et al. Nat Biotechnol. 2011; 29:143-148. Guidelines for selection of potential target sites and for use of particular TALE repeat domains (harboring NH residues at the hypervariable positions) for recognition of G bases have been proposed. See Streubel et al. Nat Biotechnol. 2012; 30:593-595.

[0122] Accordingly, in some embodiments, the TALE DBD comprises one or more repeat sequences. In some embodiments, the TALE DBD comprises about 15, or about, 16, or about 17, or about 18, or about 18.5 repeat sequences. In some embodiments, the TALE DBD repeat sequences comprise 33 or 34 amino acids.

[0123] In some embodiments, the one or more of the TALE DBD repeat sequences comprise an RVD at residue 12 or 13 of the 33 or 34 amino acids. The RVD can recognize certain base pair(s) or residue(s). In some embodiments, the RVD recognizes one base pair in the nucleic acid molecule. In some embodiments, the RVD recognizes a "C" residue in the nucleic acid molecule and is selected from HD, N(gap), HA, ND, and HI. In some embodiments, the RVD recognizes a "G" residue in the nucleic acid molecule and is selected from NN, NH, NK, HN, and NA. In some embodiments, the RVD recognizes an "A" residue in the nucleic acid molecule and is selected from NI and NS. In some embodiments, the RVD recognizes a "T" residue in the nucleic acid molecule and is selected from NG, HG, H(gap), and IG.

[0124] In embodiments, the GSHS is in an open chromatin location in a chromosome. In some embodiments, the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor; and human Rosa26 locus. In some embodiments, the GSHS is located on human chromosome 2, 4, 6, 10, 11, or 17.

[0125] In some embodiments, the GSHS is selected from TALC1, TALC2, TALC3, TALC4, TALC5, TALC7, TALC8, AVS1, AVS2, AVS3, ROSA1, ROSA2, TALER1, TALER2, TALER3, TALER4, TALER5, SHCHR2-1, SHCHR2-2, SHCHR2-3, SHCHR2-4, SHCHR4-1, SHCHR4-2, SHCHR4-3, SHCHR6-1, SHCHR6-2, SHCHR6-3, SHCHR6-4, SHCHR10-1, SHCHR10-2, SHCHR10-3, SHCHR10-4, SHCHR10-5, SHCHR11-1, SHCHR11-2, SHCHR11-3, SHCHR17-1, SHCHR17-2, SHCHR17-3, and SHCHR17-4.

[0126] In some embodiments, the GSHS comprises one or more of TGGCCGGCCTGACCACTGG (SEQ ID NO: 23), TGAAGGCCTGGCCGGCCTG (SEQ ID NO: 24), TGAGCACTGAAGGCCTGGC (SEQ ID NO: 25), TCCACTGAGCACTGAAGGC (SEQ ID NO: 26), TGGTTTCCACTGAGCACTG (SEQ ID NO: 27), TGGGGAAAATGACCCAACA (SEQ ID NO: 28), TAGGACAGTGGGGAAAATG (SEQ ID NO: 29), TCCAGGGACACGGTGCTAG (SEQ ID NO: 30), TCAGAGCCAGGAGTCCTGG (SEQ ID NO: 31), TCCTTCAGAGCCAGGAGTC (SEQ ID NO: 32), TCCTCCTTCAGAGCCAGGA (SEQ ID NO: 33), TCCAGCCCCTCCTCCTTCA (SEQ ID NO: 34), TCCGAGCTTGACCCTTGGA (SEQ ID NO: 35), TGGTTTCCGAGCTTGACCC (SEQ ID NO: 36), TGGGGTGGTTTCCGAGCTT (SEQ ID NO: 37), TCTGCTGGGGTGGTTTCCG (SEQ ID NO: 38), TGCAGAGTATCTGCTGGGG (SEQ ID NO: 39), CCAATCCCCTCAGT (SEQ ID NO: 40), CAGTGCTCAGTGGAA (SEQ ID NO: 41), GAAACATCCGGCGACTCA (SEQ ID NO: 42), TCGCCCCTCAAATCTTACA (SEQ ID NO: 43), TCAAATCTTACAGCTGCTC (SEQ ID NO: 44), TCTTACAGCTGCTCACTCC (SEQ ID NO: 45), TACAGCTGCTCACTCCCCT (SEQ ID NO: 46), TGCTCACTCCCCTGCAGGG (SEQ ID NO: 47), TCCCCTGCAGGGCAACGCC (SEQ ID NO: 48), TGCAGGGCAACGCCCAGGG (SEQ ID NO: 49), TCTCGATTATGGGCGGGAT (SEQ ID NO: 50), TCGCTTCTCGATTATGGGC (SEQ ID NO: 51), TGTCGAGTCGCTTCTCGAT (SEQ ID NO: 52), TCCATGTCGAGTCGCTTCT (SEQ ID NO: 53), TCGCCTCCATGTCGAGTCG (SEQ ID NO: 54), TCGTCATCGCCTCCATGTC (SEQ ID NO: 55), TGATCTCGTCATCGCCTCC (SEQ ID NO: 56), GCTTCAGCTTCCTA (SEQ ID NO: 57), CTGTGATCATGCCA (SEQ ID NO: 58), ACAGTGGTACACACCT (SEQ ID NO: 59), CCACCCCCCACTAAG (SEQ ID NO: 60), CATTGGCCGGGCAC (SEQ ID NO: 61), GCTTGAACCCAGGAGA (SEQ ID NO: 62), ACACCCGATCCACTGGG (SEQ ID NO: 63), GCTGCATCAACCCC (SEQ ID NO: 64), GCCACAAACAGAAATA (SEQ ID NO: 65), GGTGGCTCATGCCTG (SEQ ID NO: 66), GATTTGCACAGCTCAT (SEQ ID NO: 67), AAGCTCTGAGGAGCA (SEQ ID NO: 68), CCCTAGCTGTCCC (SEQ ID NO: 69), GCCTAGCATGCTAG (SEQ ID NO: 70), ATGGGCTTCACGGAT (SEQ ID NO: 71), GAAACTATGCCTGC (SEQ ID NO: 72), GCACCATTGCTCCC (SEQ ID NO: 73), GACATGCAACTCAG (SEQ ID NO: 74), ACACCACTAGGGGT (SEQ ID NO: 75), GTCTGCTAGACAGG (SEQ ID NO: 76), GGCCTAGACAGGCTG (SEQ ID NO: 77), GAGGCATTCTTATCG (SEQ ID NO: 78), GCCTGGAAACGTTCC (SEQ ID NO: 79), GTGCTCTGACAATA (SEQ ID NO: 80), GTTTTGCAGCCTCC (SEQ ID NO: 81), ACAGCTGTGGAACGT (SEQ ID NO: 82), GGCTCTCTTCCTCCT (SEQ ID NO: 83), CTATCCCAAAACTCT (SEQ ID NO: 84), GAAAAACTATGTAT (SEQ ID NO: 85), AGGCAGGCTGGTTGA (SEQ ID NO: 86), CAATACAACCACGC (SEQ ID NO: 87), ATGACGGACTCAACT (SEQ ID NO: 88), CACAACATTTGTAA (SEQ ID NO: 89), and ATTTCCAGTGCACA (SEQ ID NO: 90).

[0127] In some embodiments, the TALE DBD binds to one of TGGCCGGCCTGACCACTGG (SEQ ID NO: 23), TGAAGGCCTGGCCGGCCTG (SEQ ID NO: 24), TGAGCACTGAAGGCCTGGC (SEQ ID NO: 25), TCCACTGAGCACTGAAGGC (SEQ ID NO: 26), TGGTTTCCACTGAGCACTG (SEQ ID NO: 27), TGGGGAAAATGACCCAACA (SEQ ID NO: 28), TAGGACAGTGGGGAAAATG (SEQ ID NO: 29), TCCAGGGACACGGTGCTAG (SEQ ID NO: 30), TCAGAGCCAGGAGTCCTGG (SEQ ID NO: 31), TCCTTCAGAGCCAGGAGTC (SEQ ID NO: 32), TCCTCCTTCAGAGCCAGGA (SEQ ID NO: 33), TCCAGCCCCTCCTCCTTCA (SEQ ID NO: 34), TCCGAGCTTGACCCTTGGA (SEQ ID NO: 35), TGGTTTCCGAGCTTGACCC (SEQ ID NO: 36), TGGGGTGGTTTCCGAGCTT (SEQ ID NO: 37), TCTGCTGGGGTGGTTTCCG (SEQ ID NO: 38), TGCAGAGTATCTGCTGGGG (SEQ ID NO: 39), CCAATCCCCTCAGT (SEQ ID NO: 40), CAGTGCTCAGTGGAA (SEQ ID NO: 41), GAAACATCCGGCGACTCA (SEQ ID NO: 42), TCGCCCCTCAAATCTTACA (SEQ ID NO: 43), TCAAATCTTACAGCTGCTC (SEQ ID NO: 44), TCTTACAGCTGCTCACTCC (SEQ ID NO: 45), TACAGCTGCTCACTCCCCT (SEQ ID NO: 46), TGCTCACTCCCCTGCAGGG (SEQ ID NO: 47), TCCCCTGCAGGGCAACGCC (SEQ ID NO: 48), TGCAGGGCAACGCCCAGGG (SEQ ID NO: 49), TCTCGATTATGGGCGGGAT (SEQ ID NO: 50), TCGCTTCTCGATTATGGGC (SEQ ID NO: 51), TGTCGAGTCGCTTCTCGAT (SEQ ID NO: 52), TCCATGTCGAGTCGCTTCT (SEQ ID NO: 53), TCGCCTCCATGTCGAGTCG (SEQ ID NO: 54), TCGTCATCGCCTCCATGTC (SEQ ID NO: 55), TGATCTCGTCATCGCCTCC (SEQ ID NO: 56), GCTTCAGCTTCCTA (SEQ ID NO: 57), CTGTGATCATGCCA (SEQ ID NO: 58), ACAGTGGTACACACCT (SEQ ID NO: 59), CCACCCCCCACTAAG (SEQ ID NO: 60), CATTGGCCGGGCAC (SEQ ID NO: 61), GCTTGAACCCAGGAGA (SEQ ID NO: 62), ACACCCGATCCACTGGG (SEQ ID NO: 63), GCTGCATCAACCCC (SEQ ID NO: 64), GCCACAAACAGAAATA (SEQ ID NO: 65), GGTGGCTCATGCCTG (SEQ ID NO: 66), GATTTGCACAGCTCAT (SEQ ID NO: 67), AAGCTCTGAGGAGCA (SEQ ID NO: 68), CCCTAGCTGTCCC (SEQ ID NO: 69), GCCTAGCATGCTAG (SEQ ID NO: 70), ATGGGCTTCACGGAT (SEQ ID NO: 71), GAAACTATGCCTGC (SEQ ID NO: 72), GCACCATTGCTCCC (SEQ ID NO: 73), GACATGCAACTCAG (SEQ ID NO: 74), ACACCACTAGGGGT (SEQ ID NO: 75), GTCTGCTAGACAGG (SEQ ID NO: 76), GGCCTAGACAGGCTG (SEQ ID NO: 77), GAGGCATTCTTATCG (SEQ ID NO: 78), GCCTGGAAACGTTCC (SEQ ID NO: 79), GTGCTCTGACAATA (SEQ ID NO: 80), GTTTTGCAGCCTCC (SEQ ID NO: 81), ACAGCTGTGGAACGT (SEQ ID NO: 82), GGCTCTCTTCCTCCT (SEQ ID NO: 83), CTATCCCAAAACTCT (SEQ ID NO: 84), GAAAAACTATGTAT (SEQ ID NO: 85), AGGCAGGCTGGTTGA (SEQ ID NO: 86), CAATACAACCACGC (SEQ ID NO: 87), ATGACGGACTCAACT (SEQ ID NO: 88), CACAACATTTGTAA (SEQ ID NO: 89), and ATTTCCAGTGCACA (SEQ ID NO: 90).

[0128] In some embodiments, the TALE DBD comprises one or more of

TABLE-US-00002 (SEQ ID NO: 355) NH NH HD HD NH NH HD HD NG NH NI HD HD NI HD NG NH NH, (SEQ ID NO: 356) NH NI NI NH NH HD HD NG NH NH HD HD NH NH HD HD NG NH, (SEQ ID NO: 357) NH NI NH HD NI HD NG NH NI NI NH NH HD HD NG NH NH HD, (SEQ ID NO: 358) HD HD NI HD NG NH NI NH HD NI HD NG NH NI NI NH NH HD, (SEQ ID NO: 359) NH NH NG NG NG HD HD NI HD NG NH NI NH HD NI HD NG NH, (SEQ ID NO: 360) NH NH NH NH NI NI NI NI NG NH NI HD HD HD NI NI HD NI, (SEQ ID NO: 361) NI NH NH NI HD NI NH NG NH NH NH NH NI NI NI NI NG NH, (SEQ ID NO: 362) HD HD NI NH NH NH NI HD NI HD NH NH NG NH HD NG NI NH, (SEQ ID NO: 363) HD NI NH NI NH HD HD NI NH NH NI NH NG HD HD NG NH NH, (SEQ ID NO: 364) HD HD NG NG HD NI NH NI NH HD HD NI NH NH NI NH NG HD, (SEQ ID NO: 365) HD HD NG HD HD NG NG HD NI NH NI NH HD HD NI NH NH NI, (SEQ ID NO: 366) HD HD NI NH HD HD HD HD NG HD HD NG HD HD NG NG HD NI, (SEQ ID NO: 367) HD HD NH NI NH HD NG NG NH NI HD HD HD NG NG NH NH NI, (SEQ ID NO: 368) NH NH NG NG NG HD HD NH NI NH HD NG NG NH NI HD HD HD, (SEQ ID NO: 369) NH NH NH NH NG NH NH NG NG NG HD HD NH NI NH HD NG NG, (SEQ ID NO: 370) HD NG NH HD NG NH NH NH NH NG NH NH NG NG NG HD HD NH, (SEQ ID NO: 371) NH HD NI NH NI NH NG NI NG HD NG NH HD NG NH NH NH NH, (SEQ ID NO: 372) HD HD NI NI NG HD HD HD HD NG HD NI NH NG, (SEQ ID NO: 373) HD NI NH NG NH HD NG HD NI NH NG NH NH NI NI, (SEQ ID NO: 374) NH NI NI NI HD NI NG HD HD NH NH HD NH NI HD NG HD NI, (SEQ ID NO: 375) HD NH HD HD HD HD NG HD NI NI NI NG HD NG NG NI HD NI, (SEQ ID NO: 376) HD NI NI NI NG HD NG NG NI HD NI NH HD NG NH HD NG HD, (SEQ ID NO: 377) HD NG NG NI HD NI NH HD NG NH HD NG HD NI HD NG HD HD, (SEQ ID NO: 378) NI HD NI NH HD NG NH HD NG HD NI HD NG HD HD HD HD NG, (SEQ ID NO: 379) NH HD NG HD NI HD NG HD HD HD HD NG NH HD NI NH NH NH, (SEQ ID NO: 380) HD HD HD HD NG NH HD NI NH NH NH HD NI NI HD NH HD HD, (SEQ ID NO: 381) NH HD NI NH NH NH HD NI NI HD NH HD HD HD NI NH NH NH, (SEQ ID NO: 382) HD NG HD NH NI NG NG NI NG NH NH NH HD NH NH NH NI NG, (SEQ ID NO: 383) HD NH HD NG NG HD NG HD NH NI NG NG NI NG NH NH NH HD, (SEQ ID NO: 384) NH NG HD NH NI NH NG HD NH HD NG NG HD NG HD NH NI NG, (SEQ ID NO: 385) HD HD NI NG NH NG HD NH NI NH NG HD NH HD NG NG HD NG, (SEQ ID NO: 386) HD NH HD HD NG HD HD NI NG NH NG HD NH NI NH NG HD NH, (SEQ ID NO: 387) HD NH NG HD NI NG HD NH HD HD NG HD HD NI NG NH NG HD, (SEQ ID NO: 388) NH NI NG HD NG HD NH NG HD NI NG HD NH HD HD NG HD HD, (SEQ ID NO: 389) NH HD NG NG HD NI NH HD NG NG HD HD NG NI, (SEQ ID NO: 390) HD NG NK NG NH NI NG HD NI NG NH HD HD NI, (SEQ ID NO: 391) NI HD NI NN NG NN NN NG NI HD NI HD NI HD HD NG, (SEQ ID NO: 392) HD HD NI HD HD HD HD HD HD NI HD NG NI NI NN, (SEQ ID NO: 393) HD NI NG NG NN NN HD HD NN NN NN HD NI HD, (SEQ ID NO: 394) NN HD NG NG NN NI NI HD HD HD NI NN NN NI NN NI, (SEQ ID NO: 395) NI HD NI HD HD HD NN NI NG HD HD NI HD NG NN NN NN, (SEQ ID NO: 396) NN HD NG NN HD NI NG HD NI NI HD HD HD HD, (SEQ ID NO: 397) NN NN HD NI HD NN NI NI NI HD NI HD HD HD NG HD HD, (SEQ ID NO: 398) NN NN NG NN NN HD NG HD NI NG NN HD HD NG NN, (SEQ ID NO: 399) NN NI NG NG NG NN HD NI HD NI NN HD NG HD NI NG, (SEQ ID NO: 400) NI NI NH HD NG HD NG NH NI NH NH NI NH HD, (SEQ ID NO: 401) HD HD HD NG NI NK HD NG NH NG HD HD HD HD, (SEQ ID NO: 402) NH HD HD NG NI NH HD NI NG NH HD NG NI NH, (SEQ ID NO: 403) NI NG NH NH NH HD NG NG HD NI HD NH NH NI NG, (SEQ ID NO: 404) NH NI NI NI HD NG NI NG NH HD HD NG NH HD, (SEQ ID NO: 405) NH HD NI HD HD NI NG NG NH HD NG HD HD HD, (SEQ ID NO: 406) NH NI HD NI NG NH HD NI NI HD NG HD NI NH, (SEQ ID NO: 407) NI HD NI HD HD NI HD NG NI NH NH NH NH NG, (SEQ ID NO: 408) NH NG HD NG NH HD NG NI NH NI HD NI NH NH, (SEQ ID NO: 409) NH NH HD HD NG NI NH NI HD NI NH NH HD NG NH, (SEQ ID NO: 410) NH NI NH NH HD NI NG NG HD NG NG NI NG HD NH, (SEQ ID NO: 411) NN HD HD NG NN NN NI NI NI HD NN NG NG HD HD, (SEQ ID NO: 412) NN NG NN HD NG HD NG NN NI HD NI NI NG NI, (SEQ ID NO: 413) NN NG NG NG NG NN HD NI NN HD HD NG HD HD, (SEQ ID NO: 414) NI HD NI NN HD NG NN NG NN NN NI NI HD NN NG, (SEQ ID NO: 415) HD NI NI NN NI HD HD NN NI NN HD NI HD NG NN HD NG NN, (SEQ ID NO: 416)

HD NG NI NG HD HD HD NI NI NI NI HD NG HD NG, (SEQ ID NO: 417) NH NI NI NI NI NI HD NG NI NG NH NG NI NG, (SEQ ID NO: 418) NI NH NH HD NI NH NH HD NG NH NH NG NG NH NI, (SEQ ID NO: 419) HD NI NI NG NI HD NI NI HD HD NI HD NN HD, (SEQ ID NO: 420) NI NG NN NI HD NN NN NI HD NG HD NI NI HD NG, (SEQ ID NO: 421) HD NI HD NI NI HD NI NG NG NG NN NG NI NI, and (SEQ ID NO: 422) NI NG NG NG HD HD NI NN NG NN HD NI HD NI.

[0129] In some embodiments, the GSHS is selected from sites listed in FIG. 3 and the TALE DBD comprises a sequence of FIG. 3.

[0130] In some embodiments, the TALE DBD comprises one or more of the sequences of FIG. 3 or a sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0131] In some embodiments, the GSHS and the TALE DBD sequences are selected from:

TABLE-US-00003 (SEQ ID NO: 23) TGGCCGGCCTGACCACTGG and (SEQ ID NO: 355) NH NH HD HD NH NH HD HD NG NH NI HD HD NI HD NG NH NH; (SEQ ID NO: 24) TGAAGGCCTGGCCGGCCTG and (SEQ ID NO: 356) NH NI NI NH NH HD HD NG NH NH HD HD NH NH HD HD NG NH; (SEQ ID NO: 25) TGAGCACTGAAGGCCTGGC and (SEQ ID NO: 357) NH NI NH HD NI HD NG NH NI NI NH NH HD HD NG NH NH HD; (SEQ ID NO: 26) TCCACTGAGCACTGAAGGC and (SEQ ID NO: 358) HD HD NI HD NG NH NI NH HD NI HD NG NH NI NI NH NH HD; (SEQ ID NO: 27) TGGTTTCCACTGAGCACTG and (SEQ ID NO: 359) NH NH NG NG NG HD HD NI HD NG NH NI NH HD NI HD NG NH; (SEQ ID NO: 28) TGGGGAAAATGACCCAACA and (SEQ ID NO: 360) NH NH NH NH NI NI NI NI NG NH NI HD HD HD NI NI HD NI; (SEQ ID NO: 29) TAGGACAGTGGGGAAAATG and (SEQ ID NO: 361) NI NH NH NI HD NI NH NG NH NH NH NH NI NI NI NI NG NH; (SEQ ID NO: 30) TCCAGGGACACGGTGCTAG and (SEQ ID NO: 362) HD HD NI NH NH NH NI HD NI HD NH NH NG NH HD NG NI NH; (SEQ ID NO: 31) TCAGAGCCAGGAGTCCTGG and (SEQ ID NO: 363) HD NI NH NI NH HD HD NI NH NH NI NH NG HD HD NG NH NH; (SEQ ID NO: 32) TCCTTCAGAGCCAGGAGTC and (SEQ ID NO: 364) HD HD NG NG HD NI NH NI NH HD HD NI NH NH NI NH NG HD; (SEQ ID NO: 33) TCCTCCTTCAGAGCCAGGA and (SEQ ID NO: 365) HD HD NG HD HD NG NG HD NI NH NI NH HD HD NI NH NH NI; (SEQ ID NO: 34) TCCAGCCCCTCCTCCTTCA and (SEQ ID NO: 366) HD HD NI NH HD HD HD HD NG HD HD NG HD HD NG NG HD NI; (SEQ ID NO: 35) TCCGAGCTTGACCCTTGGA and (SEQ ID NO: 367) HD HD NH NI NH HD NG NG NH NI HD HD HD NG NG NH NH NI; (SEQ ID NO: 36) TGGTTTCCGAGCTTGACCC and (SEQ ID NO: 368) NH NH NG NG NG HD HD NH NI NH HD NG NG NH NI HD HD HD; (SEQ ID NO: 37) TGGGGTGGTTTCCGAGCTT and (SEQ ID NO: 369) NH NH NH NH NG NH NH NG NG NG HD HD NH NI NH HD NG NG; (SEQ ID NO: 38) TCTGCTGGGGTGGTTTCCG and (SEQ ID NO: 370) HD NG NH HD NG NH NH NH NH NG NH NH NG NG NG HD HD NH; (SEQ ID NO: 39) TGCAGAGTATCTGCTGGGG and (SEQ ID NO: 371) NH HD NI NH NI NH NG NI NG HD NG NH HD NG NH NH NH NH; (SEQ ID NO: 40) CCAATCCCCTCAGT and (SEQ ID NO: 372) HD HD NI NI NG HD HD HD HD NG HD NI NH NG; (SEQ ID NO: 41) CAGTGCTCAGTGGAA and (SEQ ID NO: 373) HD NI NH NG NH HD NG HD NI NH NG NH NH NI NI; (SEQ ID NO: 42) GAAACATCCGGCGACTCA and (SEQ ID NO: 374) NH NI NI NI HD NI NG HD HD NH NH HD NH NI HD NG HD NI; (SEQ ID NO: 43) TCGCCCCTCAAATCTTACA and (SEQ ID NO: 375) HD NH HD HD HD HD NG HD NI NI NI NG HD NG NG NI HD NI; (SEQ ID NO: 44) TCAAATCTTACAGCTGCTC and (SEQ ID NO: 376) HD NI NI NI NG HD NG NG NI HD NI NH HD NG NH HD NG HD; (SEQ ID NO: 45) TCTTACAGCTGCTCACTCC and (SEQ ID NO: 377) HD NG NG NI HD NI NH HD NG NH HD NG HD NI HD NG HD HD; (SEQ ID NO: 46) TACAGCTGCTCACTCCCCT and (SEQ ID NO: 378) NI HD NI NH HD NG NH HD NG HD NI HD NG HD HD HD HD NG; (SEQ ID NO: 47) TGCTCACTCCCCTGCAGGG and (SEQ ID NO: 379) NH HD NG HD NI HD NG HD HD HD HD NG NH HD NI NH NH NH; (SEQ ID NO: 48) TCCCCTGCAGGGCAACGCC and (SEQ ID NO: 380) HD HD HD HD NG NH HD NI NH NH NH HD NI NI HD NH HD HD; (SEQ ID NO: 49) TGCAGGGCAACGCCCAGGG and (SEQ ID NO: 381) NH HD NI NH NH NH HD NI NI HD NH HD HD HD NI NH NH NH; (SEQ ID NO: 50) TCTCGATTATGGGCGGGAT and (SEQ ID NO: 382) HD NG HD NH NI NG NG NI NG NH NH NH HD NH NH NH NI NG; (SEQ ID NO: 51) TCGCTTCTCGATTATGGGC

and (SEQ ID NO: 383) HD NH HD NG NG HD NG HD NH NI NG NG NI NG NH NH NH HD; (SEQ ID NO: 52) TGTCGAGTCGCTTCTCGAT and (SEQ ID NO: 384) NH NG HD NH NI NH NG HD NH HD NG NG HD NG HD NH NI NG; (SEQ ID NO: 53) TCCATGTCGAGTCGCTTCT and (SEQ ID NO: 385) HD HD NI NG NH NG HD NH NI NH NG HD NH HD NG NG HD NG; (SEQ ID NO: 54) TCGCCTCCATGTCGAGTCG and (SEQ ID NO: 386) HD NH HD HD NG HD HD NI NG NH NG HD NH NI NH NG HD NH; (SEQ ID NO: 55) TCGTCATCGCCTCCATGTC and (SEQ ID NO: 387) HD NH NG HD NI NG HD NH HD HD NG HD HD NI NG NH NG HD; (SEQ ID NO: 56) TGATCTCGTCATCGCCTCC and (SEQ ID NO: 388) NH NI NG HD NG HD NH NG HD NI NG HD NH HD HD NG HD HD; (SEQ ID NO: 57) GCTTCAGCTTCCTA and (SEQ ID NO: 389) NH HD NG NG HD NI NH HD NG NG HD HD NG NI; (SEQ ID NO: 58) CTGTGATCATGCCA and (SEQ ID NO: 390) HD NG NK NG NH NI NG HD NI NG NH HD HD NI; (SEQ ID NO: 59) ACAGTGGTACACACCT and (SEQ ID NO: 391) NI HD NI NN NG NN NN NG NI HD NI HD NI HD HD NG; (SEQ ID NO: 60) CCACCCCCCACTAAG and (SEQ ID NO: 392) HD HD NI HD HD HD HD HD HD NI HD NG NI NI NN; (SEQ ID NO: 61) CATTGGCCGGGCAC and (SEQ ID NO: 393) HD NI NG NG NN NN HD HD NN NN NN HD NI HD; (SEQ ID NO: 62) GCTTGAACCCAGGAGA and (SEQ ID NO: 394) NN HD NG NG NN NI NI HD HD HD NI NN NN NI NN NI; (SEQ ID NO: 63) ACACCCGATCCACTGGG and (SEQ ID NO: 395) NI HD NI HD HD HD NN NI NG HD HD NI HD NG NN NN NN; (SEQ ID NO: 64) GCTGCATCAACCCC and (SEQ ID NO: 396) NN HD NG NN HD NI NG HD NI NI HD HD HD HD; (SEQ ID NO: 65) GCCACAAACAGAAATA and (SEQ ID NO: 397) NN NN HD NI HD NN NI NI NI HD NI HD HD HD NG HD HD; (SEQ ID NO: 66) GGTGGCTCATGCCTG and (SEQ ID NO: 398) NN NN NG NN NN HD NG HD NI NG NN HD HD NG NN; (SEQ ID NO: 67) GATTTGCACAGCTCAT and (SEQ ID NO: 399) NN NI NG NG NG NN HD NI HD NI NN HD NG HD NI NG; (SEQ ID NO: 68) AAGCTCTGAGGAGCA and (SEQ ID NO: 400) NI NI NH HD NG HD NG NH NI NH NH NI NH HD; (SEQ ID NO: 69) CCCTAGCTGTCCC and (SEQ ID NO: 401) HD HD HD NG NI NK HD NG NH NG HD HD HD HD; (SEQ ID NO: 70) GCCTAGCATGCTAG and (SEQ ID NO: 402) NH HD HD NG NI NH HD NI NG NH HD NG NI NH; (SEQ ID NO: 71) ATGGGCTTCACGGAT and (SEQ ID NO: 403) NI NG NH NH NH HD NG NG HD NI HD NH NH NI NG; (SEQ ID NO: 72) GAAACTATGCCTGC and (SEQ ID NO: 404) NH NI NI NI HD NG NI NG NH HD HD NG NH HD; (SEQ ID NO: 73) GCACCATTGCTCCC and (SEQ ID NO: 405) NH HD NI HD HD NI NG NG NH HD NG HD HD HD; (SEQ ID NO: 74) GACATGCAACTCAG and (SEQ ID NO: 406) NH NI HD NI NG NH HD NI NI HD NG HD NI NH; (SEQ ID NO: 75) ACACCACTAGGGGT and (SEQ ID NO: 407) NI HD NI HD HD NI HD NG NI NH NH NH NH NG; (SEQ ID NO: 76) GTCTGCTAGACAGG and (SEQ ID NO: 408) NH NG HD NG NH HD NG NI NH NI HD NI NH NH; (SEQ ID NO: 77) GGCCTAGACAGGCTG and (SEQ ID NO: 409) NH NH HD HD NG NI NH NI HD NI NH NH HD NG NH; (SEQ ID NO: 78) GAGGCATTCTTATCG and (SEQ ID NO: 410) NH NI NH NH HD NI NG NG HD NG NG NI NG HD NH; (SEQ ID NO: 79) GCCTGGAAACGTTCC and (SEQ ID NO: 411) NN HD HD NG NN NN NI NI NI HD NN NG NG HD HD; (SEQ ID NO: 80) GTGCTCTGACAATA and (SEQ ID NO: 412) NN NG NN HD NG HD NG NN NI HD NI NI NG NI; (SEQ ID NO: 81) GTTTTGCAGCCTCC and (SEQ ID NO: 413) NN NG NG NG NG NN HD NI NN HD HD NG HD HD; (SEQ ID NO: 82) ACAGCTGTGGAACGT and (SEQ ID NO: 414) NI HD NI NN HD NG NN NG NN NN NI NI HD NN NG; (SEQ ID NO: 83) GGCTCTCTTCCTCCT and (SEQ ID NO: 415) HD NI NI NN NI HD HD NN NI NN HD NI HD NG NN HD NG NN; (SEQ ID NO: 84) CTATCCCAAAACTCT and

(SEQ ID NO: 416) HD NG NI NG HD HD HD NI NI NI NI HD NG HD NG; (SEQ ID NO: 85) GAAAAACTATGTAT and (SEQ ID NO: 417) NH NI NI NI NI NI HD NG NI NG NH NG NI NG; (SEQ ID NO: 86) AGGCAGGCTGGTTGA and (SEQ ID NO: 418) NI NH NH HD NI NH NH HD NG NH NH NG NG NH NI; (SEQ ID NO: 87) CAATACAACCACGC and (SEQ ID NO: 419) HD NI NI NG NI HD NI NI HD HD NI HD NN HD; (SEQ ID NO: 88) ATGACGGACTCAACT and (SEQ ID NO: 420) NI NG NN NI HD NN NN NI HD NG HD NI NI HD NG; and (SEQ ID NO: 89) CACAACATTTGTAA and (SEQ ID NO: 421) HD NI HD NI NI HD NI NG NG NG NN NG NI NI.

[0132] In some embodiments, the GSHS is within about 25, or about 50, or about 100, or about 150, or about 200, or about 300, or about 500 nucleotides of the TA dinucleotide site or TTAA (SEQ ID NO: 1) tetranucleotide site.

[0133] In some embodiments, guide RNAs (gRNAs) for targeting human genomic safe harbor sites using dCas in areas of open chromatin are as shown in FIG. 4.

[0134] In embodiments, the enzyme (e.g., without limitation, a transposase enzyme) is capable of inserting a transposon at a TA dinucleotide site. In some embodiments, the enzyme (e.g., without limitation, a transposase enzyme) is capable of inserting a transposon at a TTAA (SEQ ID NO: 1) tetranucleotide site.

[0135] In embodiments, the composition comprises a system having nucleic acids encoding the enzyme and the transposon, respectively. FIGS. 1A-1D show examples of a system in accordance with embodiments of the present disclosure. For example, as shown in FIG. 2, in some embodiments, the system comprises a nucleic acid (e.g., helper RNA) encoding an enzyme capable of targeted genomic integration by transposition, and a nucleic acid encoding a transposase (e.g., donor DNA). The helper RNA is translated into a bioengineered enzyme (e.g., integrase, recombinase, or transposase) that recognizes specific ends and seamlessly inserts the donor DNA into the human genome in a site-specific manner without a footprint.

[0136] In embodiments, an enzyme capable of targeted genomic integration by transposition is encoded by a first nucleic acid, and the transposon is encoded by a second, non-viral nucleic acid. The transposon comprises a transgene and is flanked by ends recognized by the enzyme, and the enzyme causes the transgene be inserted in a certain genomic locus and/or site (e.g., at a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site in a genomic safe harbor site (GSHS) of a nucleic acid molecule. In some embodiments, the first nucleic acid is RNA, for example, helper RNA; and the second, non-viral nucleic acid is DNA. In embodiments, inteins (also referred to as splicing domains) are used to synthesize a recombinant enzyme (e.g., without limitation, an MLT fusion protein) that includes desired internal DNA biding domains (DNA binders) that target specific sites within the human genome for integration of a donor transgene.

[0137] Inteins (INTervening protEINS) are mobile genetic elements that are protein domains, found in nature, with the capability to carry out the process of protein splicing. See Sarmiento & Camarero (2019) Current protein & peptide science, 20(5), 408-424, which is incorporated by reference herein in its entirety. Protein spicing is a post-translation biochemical modification which results in the cleavage and formation of peptide bonds between precursor polypeptide segments flanking the intein. Id. Inteins apply standard enzymatic strategies to excise themselves post-translationally from a precursor protein via protein splicing. Nanda et al., Microorganisms vol. 8, 12 2004. 16 Dec. 2020, doi:10.3390/microorganisms8122004. An intein can splice its flanking N- and C-terminal domains to become a mature protein and excise itself from a sequence. For example, split inteins have been used to control the delivery of heterologous genes into transgenic organisms. See Wood & Camarero (2014) J Biol Chem. 289(21):14512-14519. This approach relies on splitting the target protein into two segments, which are then post-translationally reconstituted in vivo by protein trans-splicing (PTS). See Aboye & Camarero (2012) J. Biol. Chem. 287, 27026-27032. More recently, an intein-mediated split-Cas9 system has been developed to incorporate Cas9 into cells and reconstitute nuclease activity efficiently. Truong et al., Nucleic Acids Res. 2015, 43 (13), 6450-6458. The protein splicing excises the internal region of the precursor protein, which is then followed by the ligation of the N-extein and C-extein fragments, resulting in two polypeptides--the excised intein and the new polypeptide produced by joining the C- and N-exteins. Sarmiento & Camarero (2019).

[0138] In embodiments, intein-mediated incorporation of DNA binders such as, without limitation, dCas9, dCas12j, or TALEs, allows creation of a split-MLT transposase system that permits reconstitution of the full-length MLT transposase from two smaller fragments. This allows avoiding the need to express DNA binders at the N- or C-terminus of an MLT transposase. In this approach, the two portions of an MLT transposase are fused to the intein and, after co-expression, the intein allows producing a full-length MLT transposase by post-translation modification. Thus, in embodiments, a nucleic acid encoding the enzyme capable of targeted genomic integration by transposition comprises an intein. In embodiments, the nucleic acid encodes the enzyme in the form of first and second portions with the intein encoded between the first and second portions, such that the first and second portions are fused into a functional enzyme upon post-translational excision of the intein from the enzyme.

[0139] In embodiments, an intein can be a suitable ligand-dependent intein, for example, an intein selected from those described in U.S. Pat. No. 9,200,045; Mootz et al., J. Am. Chem. Soc. 2002; 124, 9044-9045; Mootz et al., J. Am. Chem. Soc. 2003; 125, 10561-10569; Buskirk et al., Proc. Natl. Acad. Sci. USA. 2004; 101, 10505-10510; Skretas & Wood. Protein Sci. 2005; 14, 523-532; Schwartz, et al., Nat. Chem. Biol. 2007; 3, 50-54; Peck et al., Chem. Biol. 2011; 18 (5), 619-630; the entire contents of each of which are hereby incorporated by reference herein.

[0140] In embodiments the intein is NpuN (Intein-N) (SEQ ID NO: 423) and/or NpuC (Intein-C) (SEQ ID NO: 424), or a variant thereof, e.g. a sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0141] In embodiments, an enzyme capable of targeted genomic integration by transposition is, without limitation, a transposase enzyme. In embodiments, the transposase enzyme is derived from Bombyx mori, Xenopus tropicalis, or Trichoplusia ni. In embodiments, the enzyme (e.g., without limitation, a transposase enzyme) is an engineered version of a transposase enzyme, including but not limited to monomers, dimers, tetramers, hyperactive, or Int-forms, derived from Bombyx mori, Xenopus tropicalis, or Trichoplusia ni.

[0142] In embodiments, the transposase enzyme is an engineered version, including but not limited to a transposase enzyme that is a monomer, dimer, tetramer, hyperactive, or has a reduced interaction with non-TTAA (SEQ ID NO: 1) recognitions sites (Int-), derived from any of Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Myotis lucifugus, Pipistrellus kuhlii, Pteropus vampyrus, and Molossus molossus Bombyx mori, Xenopus tropicalis, Trichoplusia ni or Myotis lucifugus. The transposase enzyme can be either the wild type, monomer, dimer, tetramer, hyperactive, or an Int-mutant.

[0143] In some embodiments, the linker that connects the TALE DBD or dCas9/gRNA and the transposase enzyme is a flexible linker. In some embodiments, the flexible linker is substantially comprised of glycine and serine residues, optionally wherein the flexible linker comprises (Gly.sub.4Ser).sub.n, where n is from about 1 to about 12. The flexible linker can be about 20, or about 30, or about 40, or about 50, or about 60 amino acid residues.

[0144] In some aspects, a nucleic acid encoding a chimeric transposase in accordance with embodiments of the present disclosure is provided. The nucleic acid can be DNA or RNA. In some embodiments, the chimeric transposase is incorporated into a vector. In some embodiments, the vector is a non-viral vector.

[0145] In some aspects, a host cell comprising the nucleic acid in accordance with embodiments of the present disclosure is provided.

[0146] In some embodiments, a composition or a nucleic acid in accordance with embodiments of the present disclosure is provided wherein the composition is in the form of a lipid nanoparticle (LNP). The composition can comprise one or more lipids selected from 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), a cationic cholesterol derivative mixed with dimethylaminoethane-carbamoyl (DC-Chol), phosphatidylcholine (PC), triolein (glyceryl trioleate), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG), 1,2-dimyristoyl-rac-glycero-3-methoxypolyethyleneglycol-2000 (DMG-PEG 2K), and 1,2 distearol-sn-glycerol-3phosphocholine (DSPC) and/or comprising of one or more molecules selected from polyethylenimine (PEI) and poly(lactic-co-glycolic acid) (PLGA), and N-Acetylgalactosamine (GalNAc).

[0147] In some aspects, a method for inserting a gene into the genome of a cell is provided that comprises contacting a cell with a chimeric transposase in accordance with embodiments of the present disclosure. The method can be an in vivo or ex vivo method.

[0148] In some embodiments, the cell is contacted with a nucleic acid encoding the chimeric transposase in accordance with embodiments of the present disclosure. In some embodiments, the cell is contacted with an RNA encoding the chimeric transposase. In some embodiments, the cell is contacted with a construct comprising a transposon. In some embodiments, the cell is contacted with a DNA encoding the chimeric transposase.

[0149] In embodiments, the present method for inserting a gene into the genome of a cell utilizes the present MLT transposase, e.g. with an amino acid sequence of SEQ ID NO: 2, or a variant thereof (and optionally one or more hyperactive mutations), or the described chimera thereof, at a ratio of about 0.5:1, or a ratio of about 1:1 or a ratio of about 2:1, or a ratio of about 1:0.5, or a ratio of about 1:2, the ratio being the amount of transposon (or payload/transgene) to amount of MLT transposase or the described chimera thereof (e.g. weight:weight, concentration:concentration).

[0150] In embodiments, the present method for inserting a gene into the genome of a cell utilizes an immortalized cell line. In embodiments, the present method for inserting a gene into the genome of a cell utilizes a cell derived from a human subject (e.g. the method is performed ex vivo or invitro). In embodiments, the present method for inserting a gene into the genome of a cell utilizes a kidney cell, or a ovary cell, or an immune cell, e.g. a T cell).

[0151] In embodiments, the present method for inserting a gene into the genome allows for expression of the inserted gene. In embodiments, the present method for inserting a gene into the genome provides expression of the inserted gene for at least 7 days, or at least 8 days, or at least 9 days, or at least 10 days, or at least 14 days, or at least 21 days, or at least about 7-21 days, or at least about 7-14 days, or at least about 7-10 days, or at least about 10-14 days.

[0152] In embodiments, the present method for inserting a gene into the genome does not substantially effect recipient cell viability (e.g. at least about 95%, or at least about 90%, or at least about 85%, or at least about 80%, or at least about 75%, or at least about 50% of cells remain viable after insertion).

[0153] As would be appreciated in the art, a transposon often includes an open reading frame that encodes a transgene at the middle of transposon and terminal repeat sequences at the 5' and 3' end of the transposon. The translated transposase binds to the 5' and 3' sequence of the transposon and carries out the transposition function.

[0154] In embodiments, a transposon is used interchangeably with transposable elements, which are used to refer to polynucleotides capable of inserting copies of themselves into other polynucleotides. The term transposon is well known to those skilled in the art and includes classes of transposons that can be distinguished on the basis of sequence organization, for example inverted terminal sequences at each end, and/or directly repeated long terminal repeats (LTRs) at the ends. In some embodiments, the transposon as described herein may be described as a piggyBac like element, e.g. a transposon element that is characterized by its traceless excision, which recognizes TTAA (SEQ ID NO: 1) sequence and restores the sequence at the insert site back to the original TTAA (SEQ ID NO: 1) sequence after removal of the transposon.

[0155] In embodiments, the transposon includes a MLT transposase. In embodiments, the MLT transposase is a transposase having an amino acid sequence of SEQ ID NO: 2, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the MLT transposase is a transposase having an amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0156] In embodiments, the transposase can act on an MLT left terminal end, or a sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, wherein the nucleotide sequence of the MLT left terminal end (5' to 3') is as follows:

TABLE-US-00004 (SEQ ID NO: 21) TTAACACTTGGATTGCGGGAAACGAGTTAAGTCGGCTCGCGTGAATTGCG CGTACTCCGCGGGAGCCGTCTTAACTCGGTTCATATAGATTTGCGGTGGA GTGCGGGAAACGTGTAAACTCGGGCCGATTGTAACTGCGTATTACCAAAT ATTTGTT.

[0157] In embodiments, the transposase can act on an MLT right terminal end, or a sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, wherein the nucleotide sequence of the MLT right terminal end (5' to 3') is as follows:

TABLE-US-00005 (SEQ ID NO: 22) AATTATTTATGTACTGAATAGATAAAAAAATGTCTGTGATTGAATAAA TTTTCATTTTTTACACAAGAAACCGAAAATTTCATTTCAATCGAACCC ATACTTCAAAAGATATAGGCATTTTAAACTAACTCTGATTTTGCGCGG GAAACCTAAATAATTGCCCGCGCCATCTTATATTTTGGCGGGAAATTC ACCCGACACCGTAGTGTTAA.

[0158] In some embodiments, the transposon is flanked by one or more terminal ends. In some embodiments, the transposon is or comprises a gene encoding a compete polypeptide. In some embodiments, the transposon is or comprises a gene which is defective or substantially absent in a disease state.

[0159] In embodiments, the transposon can encode various genes. For example, in some embodiments, the transposon is an ATP Binding Cassette Subfamily A Member 4 gene (ABC) transporter gene (ABCA4), or functional fragment thereof. As another example, in some embodiments, the transposon is a very low-density lipoprotein receptor gene (VLDLR) or a low-density lipoprotein receptor gene (LDLR) or a functional fragment thereof.

[0160] In some embodiments, a therapeutic gene is inserted into a GSHS location in a host genome. GSHSs can be defined as loci well-suited for gene transfer, as integrations within these sites are not associated with adverse effects such as proto-oncogene activation, tumor suppressor inactivation, or insertional mutagenesis. GSHSs can defined by the following criteria: 1) distance of at least 50 kb from the 5' end of any gene, (2) distance of at least 300 kb from any cancer-related gene, (3) distance of at least 300 kb from any microRNA (miRNA), (4) location outside a transcription unit, and (5) location outside ultra-conserved regions (UCRs) of the human genome. See Papapetrou et al. Nat Biotechnol 2011; 29:73-8; Bejerano et al. Science 2004; 304:1321-5.

[0161] Furthermore, the use of GSHS locations can allow stable transgene expression across multiple cell types. One such site, chemokine C-C motif receptor 5 (CCR5) has been identified and used for integrative gene transfer. CCR5 is a member of the beta chemokine receptor family and is required for the entry of R5 tropic viral strains involved in primary infections. A homozygous 32 bp deletion in the CCR5 gene confers resistance to HIV-1 virus infections in humans. Disrupted CCR5 expression, naturally occurring in about 1% of the Caucasian population, does not appear to result in any reduction in immunity. Lobritz at al., Viruses 2010; 2:1069-105. A clinical trial has demonstrated safety and efficacy of disrupting CCR5 via targetable nucleases. Tebas at al., HIV. N Engl J Med 2014; 370:901-10.

[0162] The transposon can be under control of a tissue-specific promoter. The tissue-specific promoter can be, e.g., a liver-specific promoter. In some embodiments, the liver-specific promoter is an LP1 promoter that, in some embodiments, is a human LP1 promoter. The LP1 promoter is described, e.g., in Nathwani et al. Blood vol. 2006; 107(7):2653-61, and it can be constructed as described in Nathawani et al. In some embodiments, the tissue-specific promoter is retina-specific promoter, such as, e.g. a retinal pigment epithelium (RPE) promoter, which can be RPE65, IRBP, or VMD2 promoter. The RPE65, IRBP, and VMD2 promoters are described in, e.g., Aguirre. Invest Ophthalmol Vis Sci. 2017; 58(12):5399-5411. doi:10.1167/iovs.17-22978. In some embodiments, the retina-specific promoter is a photoreceptor promoter, optionally selected from .beta.-phosphodiesterase (PDE) (see, e.g. Di Polo et al., Nucleic Acids Res. 1997; 25(19):3863-3867), rhodopsin kinase (GRK1) (see, e.g. Khani et al., 2007; McDougald et al., Mol Ther Methods Clin Dev. 2019; 13:380-389. Published 2019 Mar. 28), CAR (cone arrestin) (see, e.g. McDougald et al., Mol Ther Methods Clin Dev. 2019; 13:380-389. Published 2019 Mar. 28), retinitis pigmentosa 1 (RP1), and L-opsin (see, e.g. Kan et al., Molecular Therapy, vol. 15, Suppl. 1, S258, May 1, 2007; Lee et al., Vision Res. 2008 February; 48(3):332-8).

[0163] It should be appreciated however that a variety of promoters can be used, including other tissue-specific promoters, inducible promoters, constitutive promoters, etc.

[0164] The chimeric transposase can be incorporated into a vector such as a non-viral vector. The chimeric transposase can be encoded on the same vector as a vector encoding a transposon, or it can be encoded on a separate vector plasmid or RNA.

[0165] Furthermore, various transposase enzymes can be used to construct a chimeric transposase.

[0166] In some embodiments, the transposase is from a Tcl/mariner transposon system. See, e.g. Plasterk et al. Trends in Genetics. 1999; 15(8):326-32.

[0167] In some embodiments, the promoter is a cytomegalovirus (CMV) enhancer fused to the chicken .beta.-actin (CAG) promoter. See Alexopoulou et al., BMC Cell Biol. 2008; 9:2, published online Jan. 11, 2008.

[0168] In some embodiments, the transposase is from a Sleeping Beauty transposon system (see, e.g., Cell. 1997; 91:501-510), e.g. a hyperactive form of Sleeping Beauty (hypSB), e.g. SB100X (see Gene Therapy volume 18, pages 849-856(2011), or a piggyBac (PB) transposon system (see, e.g. Trends Biotechnol. 2015 September; 33(9):525-33, which is incorporated herein by reference in its entirety), e.g. a hyperactive form of PB transposase (hypPB), e.g. with seven amino acid substitutions (e.g. I30V, S103P, G165S, M282V, S509G, N570S, N538K on mPB, or functional equivalents in non-mPB, see Mol Ther Nucleic Acids. 2012 October; 1(10): e50, which is incorporated herein by reference in its entirety); see also Yusa et al., PNAS Jan. 25, 2011 108 (4) 1531-1536; Voigt et al., Nature Communications volume 7, Article number: 11126 (2016).

[0169] The piggyBac transposases belong to the IS4 transposase family. De Palmenaer et al., BMC Evolutionary Biology. 2008; 8:18. doi: 10.1186/1471-2148-8-18. The piggyBac family includes a large diversity of transposons, and any of these transposons can be used in embodiments of the present disclosure. See, e.g., Bouallegue et al., Genome Biol Evol. 2017; 9(2):323-339. The founding member of the piggyBac (super)family, insect piggyBac, was originally identified in the cabbage looper moth (Trichoplusiani ni) and studied both in vivo and in vitro. Insect piggyBac is known to transpose by a canonical cut-and-paste mechanism promoted by an element-encoded transposase with a catalytic site resembling the RNase H fold shared by many recombinases. The insect piggyBac transposon system has been shown to be highly active in a wide range of animals, including Drosophila and mice, where it has been developed as a powerful tool for gene tagging and genome engineering. Other transposons affiliated to the piggyBac superfamily are common in arthropods and vertebrates including Xenopus and Bombyx. Mammalian piggyBac transposons and transposases, including hyperactive mammalian piggyBac variants, which can be used in embodiments of the present disclosure, are described, e.g., in International Application WO2010085699, which is incorporated herein by reference in its entirety.

[0170] In some embodiments, the transposase is from a MLT transposon system that is based on a cut-and-paste MLT element obtained from the little brown bat (Myotis lucifugus) or other bat transposases, such as Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus. See Mitra et al., Proc Natl Acad Sci USA. 2013 Jan. 2; 110(1):234-9; Jebb et al., Nature, volume 583, pages 578-584 (2020), which is incorporated by reference herein in its entirety. In some embodiments, hyperactive forms of a bat transposase is used. The MLT transposase has been shown to be capable of transposition in bat, human, and yeast cells. The hyperactive forms of the MLT transposase enhance the transposition process. In addition, chimeric MLT transposases are capable of site-specific excision without genomic integration.

[0171] Furthermore, in embodiments, the engineered and/or corrected MLT transposase is used that has certain mutations relative to the wild-type MLT transposase. In embodiments, hyperactive forms of the corrected MLT transposase are used.

[0172] In embodiments, the transposase enzyme is derived from any of Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Myotis lucifugus, Pipistrellus kuhlii, Pteropus vampyrus, and Molossus molossus. In embodiments, the transposase enzyme is derived from any of Trichoplusia ni, Myotis lucifugus, Myotis myotis, or Pteropus vampyrus (see FIG. 7). The transposases can have one or more hyperactive and/or integration deficient mutations selected from FIGS. 5A and 5B, or equivalents thereof. One skilled in the art can correspond such mutants to transposases from any of Trichoplusia ni, Myotis lucifugus, Myotis myotis, or Pteropus vampyrus, with reference to FIG. 7.

[0173] The amino acid sequences shown in the alignment of FIG. 7 are as follows (where notations in parentheses are for distinguishing between different types of sequences only):

TABLE-US-00006 Trichnoplusia ni (SEQ ID NO: 10) 1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEI SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG 61 SEILDEQNVI EQPGSSLASN KILTLPQRTI RGKNKHCWST SKSTRRSRVS ALNIVRSQRG 121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTGATFRD TNEDEIYAFF 181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV 241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RMYIPNKPSK YGIKILMMCD 301 SGTKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVRGSC RNITCDNWFT SIPLAKNLLQ 361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC 421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN 481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMSL TSSFMRKRLE APTLKRYLRD NISNILPNEV 541 PGTSDDSTEE PVTKKRTYCT YCPSKIRRKA NASCKKCKKV ICREHNIDMC QSCF Pteropus vampyrus (SEQ ID NO: 11) 1 MSNPRKRSIP TCDVNFVLEQ LLAEDSFDES DFSEIDDSDD FSDSASEDYT VRPPSDSESD 61 GNSPTSADSG RALKWSTRVM IPRQRYDFTG TPGRKVDVSD TTDPLQYFEL FFTEELVSKI 121 TSEMNAQAAL LASKPPGPKG FSRMDKWKDT DNDELKVFFA VMLLQGIVQK PELEMFWSTR 181 PLLDIPYLRQ IMTGERFLLL LRCLHFVNNS SISAGQSKAQ ISLQKIKPVF DFLVNKFSTV 241 YTPNRNIAVD ESLMLFKGRL AMKQYIPTKM NLKDSADGLK Myotis myotis ("2a") (SEQ ID NO: 12) 1 MDLRCQHTVL SIRESRGLLP NLKMKTSRMK KGDIIFSRKG DILLLAWKDK RVVRMISIHD 61 TSVSTTGKKN RKTGENIVKP ACIKEYNAHM KGVDRADQFL SCCSILRKMM KWTKKVVLYL 121 INCGLFNSFR VYNVLNPQAK MKYKQFLLSV ARDWIMDDNN EGSPEPETNL SSPSPGGARR 181 APRKDPPKRL SGDMKQHEPT CIPASGKKKF PTRACRVCAH GKRSESRYLC KFCLVPLHRG 241 KCFTQYHTLK KY Myotis myotis ("1") (SEQ ID NO: 13) 1 MKAFLGVILN MGVLNHPNLQ SYWSMDFESH IPFFRSVFKR ERFLQIFWML HLKNDQKSSK 61 DLRTRTEKVN CFLSYLEMKF RERFCPGREI AVDEAVVGFK GKIHFITYNP KKPTKWGIRL 121 YVLSDSKCGY VHSFVPYYGG ITSETLVRPD LPFTSRIVLE LHERLKNSVP GSQGYHFFTD 181 RYYTSVTLAK ELFKEKTHLT GTIMPNRKDN PPVIKHQKLK KGEIVAFRDE NVMLLAWKDK 241 RIVTLSTWDS ETESVERRVG GGKEIVLKPK VVTNYTKFMG GVDIADYTST YCFMRKTLKW 301 WRTLFFWGLE VSVVNSYILY KECQKRKNEK PITHVKFIRK LVHDLVGEFR DGTLTSRGRL 361 LSTNLEQRLD GKLHIITPHP NKKHKDCVVC SNRKIKGGRR ETIYICETCE CKPGLHVGEC 421 FKKYHTMKNY RD Myotis lucifugus ("2") (SEQ ID NO: 14) 1 MPSLRKRKET NETDTLPEVF NDNLSDIPSE IEDADDCFDD SGDDSTDSTD SEIIRPVRKR 61 KVAVLSSDSD TDEATDNCWS EIDTPPRLQM FEGHAGVTTF PSQCDSVPSV TNLFFGDELF 121 EMLCKELSNY HDQTAMKRKT PSRTLKWSPV TQKDIKKFLG LIILMGQTRK DSLKDYWSTD 181 PLICTPIFPQ TMSRHRFEQI WTFWHFNDNA KMDSRSGRLF KIQPVLDYFL HKFRTIYKPK 241 QQLSLDEGMI PWRGRFKFRT YNPAKITKYG LLVRMVCESD TGYICSMEIY TAEGRKLQET 301 VLSVLGPYLG IWHHIYQDNY YNATSTAELL LQNKTRVCGT IRESRGLPPN LEMKTSRMKK 361 GDIIFSRKGD ILLLAWKDKR VVRMISTIHD TSVSTTGKKN RKTGENIVKP TCIKEYNAHM 421 KGVDRADQFL SCCSILRKTM KWTKKVVLYL INCGLFNSFR VYNVLNPQAK MKYKQFLLSV 481 ARDWITDDNN EGSPEPETNL SSPSPGGARR APRKDPPKRL SGDMKQHEPT CIPASGKKKF 541 PTRACRVCAA HGKRSESRYL CKFCLVPLHR GKCFTQYHTL KKYMDLRCQH TVLSTVGRGY 601 SVLARFKPRT NERTGSSHCH VQVPAGGQGP PSTIIANGCG CKLEPMVRTR SPTCLVIEFG 661 CM Myotis myotis ("2") (SEQ ID NO: 15) 1 MPSLRKRKET NETDTLPEVF NDNLSDIPSE IEDADDCFDD SGDDSTDSTE SEIIRPVRKR 61 KVAVLSSDSN TDEATDNCWS EIDTPPRLQM FEGHAGVTTF PSQCDSVPSV TNLFFGDELF 121 EMLCKELSNY HDQTAMKRKT PSRTLKWSPV TQKDIKKFLG LIILMGQTRK DSWKDYWSTD 181 PLICTPIFPQ TMSRHRFEQI WTFWHFNDNA KMDSCSGRLF KIQPVLDYFL HKFRTIYKPK 241 QQLSLDEGMI PWRGRLKFTY NPAITKYGLL VRMVCESDTG YICNMEIYTA ERKKLQETVL 301 SVLGPYLGIW HHIYQDNYYN ATSTAELLLQ NKTRVCGTIR ESRGLPPNLK MKTSRMKKGD 361 IIFSRKGDIL LLAWKDKRVV RMISTIHDTS VSTTGKKNRK TGENIVKPTC IKEYNAHMKG 421 VDRADQFLSC CSILRKTTKW TKKVVLYLIN CGLFNSFRVY NILNPQAKMK YKQFLLSVAR 481 DWITDDNNEG SPEPETNLSS PSSGGARRAP RKDQPKRLSG DMKQHEPTCI PASGKKKFPT 541 ACRVCAAHGK RSESRYLRKF CFVPLRGKCF MYHTLKKYSE LFSLIVVSKI QNVIIYKTTK 601 VYMRYVMRSH CPLSFLVFAP SVKDRSRVFS FFTRHLLWTL DVNTLSCPHR MKRSHWWKPC 661 RSIYEKLYNC TNP Myotis myotis ("2b") (SEQ ID NO: 16) 1 MDLRCQHTVL SIRESRGLPP NLKMKTSRMK KGDIIFSRKG DILLLAWKDK RVVRMISTIH 61 DTSVSTTGKK NRKTGENIVK PACIKEYNAH MKGVDRADQF LSCCSILRKT MKWTKKVVLY 121 LINCGLFNSF RVYNVLNPQA KMKYKQFLLS VARDWITDDN NEGSPEPETN LSSPSPGGAR 181 RAPRKDPPKR LSGDMKQHEP TCIPASGKKK FPTRACRVCA AHGKRSESRY LCKFCLVPLH 241 RGKCFTQYHT LKKY

[0174] 50 In embodiments, one skilled in the art can correspond such mutants to transposases from any of Bombyx mori, Xenopus tropicalis, Trichoplusia ni, Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Myotis lucifugus, Pipistrellus kuhlii, Pteropus vampyrus, and Molossus molossus.

[0175] In some embodiments, the transposase enzyme can have a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity to a nucleotide sequence of any of Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Myotis lucifugus, Pteropus vampyrus, Pipistrellus kuhlii, Pan troglodytes, Molossus molossus, or Homo sapiens. In some embodiments, the transposase enzyme can have an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity to an amino acid sequence of any of Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Myotis lucifugus, Pteropus vampyrus, Pipistrellus kuhlii, Pan troglodytes, Molossus molossus, or Homo sapiens. See Jebb, et al. (2020).

[0176] In some embodiments, a wild type MLT transposase is encoded by the following nucleotide sequence:

TABLE-US-00007 (SEQ ID NO: 5) ATGTCGCAGCATTCAGACTATTCTCATGATGAGTTTTGTGCAGACAAG TTGTCCAATTATTCTTGTGATAGCGATCTTGAAAATGCGAGTACAAGT GATGAAGATTCTAGTGATGATGAAGTAATGGTGCGTCCCAGGACATTG AGGCGACGAAGAATTTCGAGCTCCAGCTCTGACTCAGAGTCAGATATA GAAGGCGGGAGAGAAGAATGGTCGCATGTTGATAATCCACCGGTCTTA GAAGATTTTTTAGGGCATCAAGGATTAAACACAGATGCTGTTATAAAT AATATAGAAGATGCCGTGAAATTATTTATCGGAGATGATTTTTTTGAA TTTCTTGTAGAGGAGTCAAACAGGTATTATAATCAAAATAGGAATAAT TTCAAACTTTCAAAAAAAAGCCTAAAGTGGAAAGATATAACCCCTCAA GAGATGAAGAAGTTTTTAGGGTTAATTGTTCTCATGGGACAGGTGCGC AAAGATAGAAGAGATGACTATTGGACCACGGAGCCATGGACGGAGACG CCATATTTTGGTAAAACGATGACGAGAGACAGGTTCCGACAGATATGG AAAGCTTGGCACTTCAATAATAATGCGGATATCGTAAATGAATCAGAT AGACTTTGCAAAGTGAGACCAGTACTAGATTATTTTGTGCCTAAATTT ATAAATATTTACAAACCTCATCAGCAATTATCACTAGATGAAGGGATC GTACCTTGGAGGGGAAGATTATTCTTTAGGGTATATAATGCTGGCAAG ATCGTTAAATATGGAATATTGGTTCGTTTGTTGTGCGAAAGTGATACA GGATATATCTGTAACATGGAAATTTATTGCGGCGAAGGAAAGCGATTA TTGGAAACGATACAAACAGTAGTGTCTCCATACACTGATTCGTGGTAC CATATATATATGGACAATTATTATAATAGCGTCGCAAATTGTGAAGCA CTTATGAAAAACAAATTCAGAATATGTGGAACAATCCGGAAAAATCGA GGTATACCTAAAGATTTTCAAACAATTTCTTTGAAAAAAGGTGAAACA AAATTTATAAGGAAAAATGATATATTGTTACAAGTGTGGCAATCAAAA AAGCCTGTATACCTGATTTCTTCGATTCATTCTGCGGAGATGGAAGAA AGTCAGAATATTGACAGAACATCAAAAAAGAAAATTGTCAAACCGAAT GCACTCATTGACTACAATAAACATATGAAAGGTGTTGACCGGGCCGAC CAATACCTTTCATATTATTCGATATTGCGGAGGACGGTCAAATGGACA AAAAGGTTGGCAATGTATATGATAAATTGCGCATTATTTAATTCTTAT GCAGTTTACAAATCAGTGAGGCAAAGAAAAATGGGTTTTAAAATGTTT TTGAAACAAACAGCTATCCACTGGTTGACGGATGATATTCCAGAGGAC ATGGACATTGTTCCAGACCTTCAACCAGTACCGTCTACTTCTGGAATG CGGGCTAAACCACCTACATCTGATCCACCATGCAGGCTATCGATGGAC ATGAGAAAGCATACGTTACAGGCAATTGTCGGAAGTGGAAAAAAGAAA AACATTTTGAGAAGGTGTCGCGTATGTTCCGTTCATAAATTGCGCAGT GAGACACGCTACATGTGCAAATTTTGCAATATACCTCTACATAAAGGG GCGTGTTTTGAAAAATATCATACGCTAAAAAACTAT,

or a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0177] In some embodiments, a wild type MLT transposase, encoded by the nucleotide sequence of SEQ ID NO: 5 (above), has the following amino acid sequence:

TABLE-US-00008 (SEQ ID NO: 4) MSQHSDYSDDEFCADKLSNYSCDSDLENASTSDEDSSDDEVMVRPRTL RRRRISSSSSDSESDIEGGREEWSHVDNPPVLEDFLGHQGLNTDAVIN NIEDAVKLFIGDDFFEFLVEESNRYYNQNRNNFKLSKKSLKWKDITPQ EMKKFLGLIVLMGQVRKDRRDDYWITEPWTETPYFGKTMTRDRFRQIW KAWHENNNADIVNESDRLCKVRPVLDYFVPKFINIYKPHQQLSLDEGI VPWRGRLFFRVYNAGKIVKYGILVRLLCESDTGYICNMEIYCGEGKRL LETIQTWSPYTDSWYHIYMDNYYNSVANCEALMKNKFRICGTIRKNRG IPKDFQTISLKKGETKFIRKNDILLQVWQSKKPVYLISS1HSAEMEES QNIDRTSKKKIVKPNALIDYNKHMKGVDRADQYLSYYSILRRWKWTKR LAMYMINCALFNSYAVYKSVRQRKMGFKMELKQTA1HWLTDDIPEDMD IVPDLQPVPSTSGMRAKPPTSDPPCRLSMDMRKHTLQAIVGSGKKKNI LRRCRVCSVHKLRSETRYMCKFCNIPLHKGACFEKYHTLKNY,

or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0178] In some embodiments, an MLT transposase has the immediately above amino acid sequence (SEQ ID NO: 4) and includes a hyperactive mutation selected from FIG. 5A or FIG. 5B. For example, a MLT transposase can include about 1, or about 2, or about 3, or about 4, or about 5 hyperactive mutations selected from FIG. 5A or FIG. 5B, or combinations thereof.

[0179] In embodiments, an MLT transposase comprises one or more mutations selected from L573X, E574X, and S2X, wherein X is any amino acid or no amino acid, optionally X is A, G, or a deletion, optionally the mutations are L573del, E574del, and S2A.

[0180] In embodiments, an MLT transposase comprises L573del, E574del, and S2A mutations, and comprises an amino acid sequence of SEQ ID NO: 2:

TABLE-US-00009 (SEQ ID NO: 2) MAQHSDYSDDEFCADKLSNYSCDSDLENASTSDEDSSDDEVMVRPRTL RRRRISSSSSDSESDIEGGREEWSHVDNPPVLEDFLGHQGLNTDAVIN NIEDAVKLFIGDDFFEFLVEESNRYYNQNRNNFKLSKKSLKWKDITPQ EMKKFLGLIVLMGQVRKDRRDDYWITEPWTETPYFGKTMTRDRFRQIW KAWHENNNADIVNESDRLCKVRPVLDYFVPKFINIYKPHQQLSLDEGI VPWRGRLFFRVYNAGKIVKYGILVRLLCESDTGYICNMEIYCGEGKRL LETIQTVVSPYTDSWYHIYMDNYYNSVANCEALMKNKFRICGTIRKNR GIPKDFQTISLKKGETKFIRKNDILLQVWQSKKPVYLISSIHSAEMEE SQNIDRTSKKKIVKPNALIDYNKHMKGVDRADQYLSYYSILRRTVKWT KRLAMYMINCALENSYAVYKSVRQRKMGFKMFLKQTAIHWLTDDIPED MDIVPDLQPVPSTSGMRAKPPTSDPPCRLSMDMRKHTLQAIVGSGKKK NILRRCRVCSVHKLRSETRYMCKFCNIPLHKGACFEKYHTLKNY,

or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0181] The MLT transposase comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof, was engineered to improve upon the enzymes of Mitra et al. (Proc Natl Acad Sci USA. 2013 Jan. 2; 110(1):234-9) and WO2010085699, which are both incorporated by reference herein in their entireties. The MLT transposase comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof (with mutations L573del, E574del, and S2A), is referred to herein as an "engineered" and/or "corrected" MLT transposase.

[0182] In some embodiments, an MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 is encoded by the following nucleotide sequence:

TABLE-US-00010 (SEQ ID NO: 3) ATGGCCCAGCACAGCGACTACAGCGACGACGAGTTCTGTGCCGATAAG CTGAGTAACTACAGCTGCGACAGCGACCTGGAAAACGCCAGCACATCC GACGAGGACAGCTCTGACGACGAGGTGATGGTGCGGCCCAGAACCCTG AGACGGAGAAGAATCAGCAGCTCTAGCAGCGACTCTGAATCCGACATC GAGGGCGGCCGGGAAGAGTGGAGCCACGTGGACAACCCTCCTGTTCTG GAAGATTTTCTGGGCCATCAGGGCCTGAACACCGACGCCGTGATCAAC AACATCGAGGATGCCGTGAAGCTGTTCATAGGAGATGATTTCTTTGAG TTCCTGGTCGAGGAATCCAACCGCTATTACAACCAGAATAGAAACAAC TTCAAGCTGAGCAAGAAAAGCCTGAAGTGGAAGGACATCACCCCTCAG GAGATGAAAAAGTTCCTGGGACTGATCGTTCTGATGGGACAGGTGCGG AAGGACAGAAGGGATGATTACTGGACAACCGAACCTTGGACCGAGACC CCTTACTTTGGCAAGACCATGACCAGAGACAGATTCAGACAGATCTGG AAAGCCTGGCACTTCAACAACAATGCTGATATCGTGAACGAGTCTGAT AGACTGTGTAAAGTGCGGCCAGTGTTGGATTACTTCGTGCCTAAGTTC ATCAACATCTATAAGCCTCACCAGCAGCTGAGCCTGGATGAAGGCATC GTGCCCTGGCGGGGCAGACTGTTCTTCAGAGTGTACAATGCTGGCAAG ATCGTCAAATACGGCATCCTGGTGCGCCTTCTGTGCGAGAGCGATACA GGCTACATCTGTAATATGGAAATCTACTGCGGCGAGGGCAAAAGACTG CTGGAAACCATCCAGACCGTCGTTTCCCCTTATACCGACAGCTGGTAC CACATCTACATGGACAACTACTACAATTCTGTGGCCAACTGCGAGGCC CTGATGAAGAACAAGTTTAGAATCTGCGGCACAATCAGAAAAAACAGA GGCATCCCTAAGGACTTCCAGACCATCTCTCTGAAGAAGGGCGAAACC AAGTTCATCAGAAAGAACGACATCCTGCTCCAAGTGTGGCAGTCCAAG AAACCCGTGTACCTGATCAGCAGCATCCATAGCGCCGAGATGGAAGAA AGCCAGAACATCGACAGAACAAGCAAGAAGAAGATCGTGAAGCCCAAT GCTCTGATCGACTACAACAAGCACATGAAAGGCGTGGACCGGGCCGAC CAGTACCTGTCTTATTACTCTATCCTGAGAAGAACAGTGAAATGGACC AAGAGACTGGCCATGTACATGATCAATTGCGCCCTGTTCAACAGCTAC GCCGTGTACAAGTCCGTGCGACAAAGAAAAATGGGATTCAAGATGTTC CTGAAGCAGACAGCCATCCACTGGCTGACAGACGACATTCCTGAGGAC ATGGACATTGTGCCAGATCTGCAACCTGTGCCCAGCACCTCTGGTATG AGAGCTAAGCCTCCCACCAGCGATCCTCCATGTAGACTGAGCATGGAC ATGCGGAAGCACACCCTGCAGGCCATCGTCGGCAGCGGCAAGAAGAAG AACATCCTTAGACGGTGCAGGGTGTGCAGCGTGCACAAGCTGCGGAGC GAGACTCGGTACATGTGCAAGTTTTGCAACATTCCCCTGCACAAGGGA GCCTGCTTCGAGAAGTACCACACCCTGAAGAATTACTAG,

or a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0183] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more hyperactive mutations selected from FIG. 5A or FIG. 5B. For example, a MLT transposase can include about 1, or about 2, or about 3, or about 4, or about 5 hyperactive mutations selected from FIG. 5A or FIG. 5B, or combinations thereof.

[0184] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more hyperactive mutations selected from a substitution or deletion at one or more of positions S5, S8, D9, D10, E11, C13, A14, S36, S54, N125, K130, G239, T294, T300, I345, R427, D475, M481, P491, A520, and A561.

[0185] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more hyperactive mutations selected from S5P, S8P, S8P/C13R, D9G, D10G, E11G, C13R, A14V, S36G, S54N, N125K, K130T, G239S, T294A, T300A, I345V, R427H, D475G, M481V, P491Q, A520T, and A561T.

[0186] In embodiments, the MLT transposase comprises one or more of hyperactive mutants selected from S8X.sub.1, C13X.sub.2 and/or N125X.sub.3 (e.g., all of S8X.sub.1, C13X.sub.2 and N125X.sub.3, S8X.sub.1 and C13X.sub.2, S8X.sub.1 and N125X.sub.3, and C13X.sub.2 and N125X.sub.3), where X.sub.1, X.sub.2, and X.sub.3 is each independently any amino acid, or X.sub.1 is a non-polar aliphatic amino acid, selected from G, A, V, L, I and P, X.sub.2 is a positively charged amino acid selected from K, R, and H, and/or X.sub.3 is a positively charged amino acid selected from K, R, and H. In embodiments, X.sub.1 is P, X.sub.2 is R, and/or X.sub.3 is K.

[0187] In some embodiments, an MLT transposase is encoded by a nucleotide sequence (SEQ ID NO: 6) that corresponds to an amino acid (SEQ ID NO: 7) having the N125K mutation relative to the amino acid sequence of SEQ ID NO: 2 or a functional equivalent thereof:

TABLE-US-00011 (SEQ ID NO: 6) 1 atggcccagc acagcgacta cagcgacgac gagttctgtg ccgataagct gagtaactac 61 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 121 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 181 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 241 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 301 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 361 tattacaacc agaagagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 421 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 481 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 541 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 601 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 661 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 721 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 781 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 841 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 901 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 961 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1021 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1081 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1141 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1201 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1261 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1321 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1381 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1441 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1501 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1561 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1621 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1681 gcctgcttcg agaagtacca caccctgaag aattactag,

or a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto (the codon corresponding to the N125K mutation is underlined and bolded).

TABLE-US-00012 (SEQ ID NO: 7) 1 MAQHSDYSDD EFCADKLSNY SCDSDLENAS TSDEDSSDDE VMVRPRTLRR RRISSSSSDS 61 ESDIEGGREE WSHVDNPPVL EDFLGHQGLN TDAVINNIED AVKLFIGDDF FEFLVEESNR 121 ##STR00001## 181 KTMTRDRFRQ IWKAWHFNNN ADIVNESDRL CKVRPVLDYF VPKFINIYKP HQQLSLDEGI 241 VPWRGRLFFR VYNAGKIVKY GILVRLLCES DTGYICNMEI YCGEGKRLLE TIQTVVSPYT 301 DSWYHIYMDN YYNSVANCEA LMKNKFRICG TIRKNRGIPK DFQTISLKKG ETKFIRKNDI 361 LLQVWQSKKP VYLISSIHSA EMEESQNIDR TSKKKIVKPN ALIDYNKHMK GVDRADQYLS 421 YYSILRRTVR WTKRLAMYMI NCALFNSYAV YKSVRQRKMG FKMFLKQTAI HWLTDDIPED 481 MDIVPDLQPV PSTSGMRAKP PTSDPPCRLS MDMRKHTLQA IVGSGKKHNI LRRCRVSVH 541 KLRSETRYMC KFCNIPLHKG ACFEKYHTLK NY,

or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto (the amino acid corresponding to the N125K mutation is underlined and bolded).

[0188] In some embodiments, the MLT transposase encoded by the nucleotide sequence of SEQ ID NO: 7 and having the amino acid sequence of SEQ ID NO: 7 is referred to as an MLT transposase 1 (or MLT1).

[0189] In some embodiments, an MLT transposase is encoded by a nucleotide sequence (SEQ ID NO: 8) that corresponds to an amino acid (SEQ ID NO: 9) having the S8P and C13R mutations relative to the amino acid sequence of SEQ ID NO: 2 or a functional equivalent thereof:

TABLE-US-00013 (SEQ ID NO: 8) 1 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 61 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 121 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 181 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 241 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 301 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 361 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 421 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 481 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 541 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 601 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 661 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 721 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 781 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 841 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 901 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 961 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1021 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1081 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1141 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1201 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1261 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1321 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1381 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1441 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1501 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1561 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1621 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1681 gcctgcttcg agaagtacca caccctgaag aattactag,

or a nucleotide sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto (the codons corresponding to the S8P and C13R mutations are underlined and bolded).

TABLE-US-00014 (SEQ ID NO: 9) 1 MAQHSDYPDD EFRADKLSNY SCDSDLENAS TSDEDSSDDE VMVRPRTLRR RRISSSSSDS 61 ESDIEGGREE WSHVDNPPVL EDFLGHQGLN TDAVINNIED AVKLFIGDDF FEFLVEESNR 121 YYNQNRNNFK LSKKSLKWKD ITPQEMKKFL GLIVLMGQVR KDRRDDYWTT EPWTETPYFG 181 KTMTRDRFRQ IWKAWHFNNN ADIVNESDRL CKVRPVLDYF VPKFINIYKP HQQLSLDEGI 241 VPWRGRLFFR VYNAGKIVKY GILVRLLCES DTGYICNMEI YCGEGKRLLE TIQTVVSPYT 301 DSWYHIYMDN YYNSVANCEA LMKNKFRICG TIRKNRGIPK DFQTISLKKG ETKFIRKNDI 361 LLQVWQSKKP VYLISSIHSA EMEESQNIDR TSKKKIVKPN ALIDYNKHMK GVDRADQYLS 421 YYSILRRTVK WTKRLAMYMI NCALFNSYAV YKSVRQRKMG FKMFLKQTAI HWLTDDIPED 481 MDIVPDLQPV PSTSGMRAKP PTSDPPCRLS MDMRKHTLQA IVGSGKKKNI LRRCRVCSVH 541 KLRSETRYMC KFCNIPLHKG ACFEKYHTLK NY,

or an amino acid sequence having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto (the amino acids corresponding to the S8P and C13R mutations are underlined and bolded).

[0190] In some embodiments, the MLT transposase encoded by the nucleotide sequence of SEQ ID NO: 8 and having the amino acid sequence of SEQ ID NO: 9 is referred to as an MLT transposase 2 (or MLT2).

[0191] In aspects, there is provided a composition comprising a transposase enzyme (e.g. an MLT transposase) having an amino acid sequence of SEQ ID NO: 2 and a substitution at position S2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the substitution is a non-polar aliphatic amino acid, optionally one of G, A, V, L, I and P, optionally S2A. In embodiments, the enzyme does not have additional residues at the C terminus. In embodiments, the enzyme has one or more mutations which confer hyperactivity, e.g. selected from S8X.sub.1, C13X.sub.2 and/or N125X.sub.3, e.g. and where X.sub.1 is selected from G, A, V, L, I and P, X.sub.2 is selected from K, R, and H, and X.sub.3 is selected from K, R, and H, e.g. X.sub.1 is P, X.sub.2 is R, and/or X.sub.3 is K. In embodiments, there is provided a composition comprising a nucleic acid encoding the transposase enzyme (e.g. an MLT transposase) described here, e.g. having a nucleotide sequence of SEQ ID NO: 3, or a nucleotide sequence having at least about 80%, at least about 90%, or at least about 93%, or at least about 95%, or at least about 98% identity thereto. In embodiments, the transposase or nucleic acid is in the form of a lipid nanoparticle (LNP). In embodiments, the enzyme is co-formulated with a nucleic acid encoding a transposon, e.g. in the same lipid nanoparticle (LNP). In embodiments, the co-formulation comprises the nucleic acid encoding the enzyme and the nucleic acid encoding the transposon.

[0192] In embodiments, there is provided a method for inserting a gene into the genome of a cell, comprising contacting a cell with the composition comprising a transposase enzyme (e.g. an MLT transposase) having an amino acid sequence of SEQ ID NO: 2 and a substitution at position S2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, or the nucleotide sequence having at least about 80%, at least about 90%, or at least about 93%, or at least about 95%, or at least about 98% identity thereto. In embodiments, the substitution is a non-polar aliphatic amino acid, optionally one of G, A, V, L, I and P, optionally S2A. In embodiments, the enzyme does not have additional residues at the C terminus. In embodiments, the enzyme has one or more mutations which confer hyperactivity, e.g. selected from S8X.sub.1, C13X.sub.2 and/or N125X.sub.3, e.g. and where X.sub.1 is selected from G, A, V, L, I and P, X.sub.2 is selected from K, R, and H, and X.sub.3 is selected from K, R, and H, e.g. X.sub.1 is P, X.sub.2 is R, and/or X.sub.3 is K. In embodiments, the method further comprises contacting the cell with a construct comprising a transposon and/or the enzyme is co-formulated with a nucleic acid encoding a transposon (e.g. in an LNP). In embodiments, the co-formulation comprises the nucleic acid encoding the enzyme and the nucleic acid encoding the transposon.

[0193] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more mutations selected from S8P and/or C13R and one of R164N, W168V, M278A, K286A, R287A, R333A, K334A, N335A, K349A, K350A, K368A, K369A, and D416N.

[0194] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more mutations selected from S8P and/or C13R and one of R164N, W168V, M278A, K286A, R287A, R333A, K334A, N335A, K349A, K350A, K368A, K369A, and D416N and/or one or more of E284A, K286A, R287A, N310A, R333A, K334A, R336A, K349A, K350A, K368A, and K369A.

[0195] In some embodiments, a MLT transposase comprising the amino acid sequence of SEQ ID NO: 2 includes one or more mutations selected from S8P and/or C13R and one of R164N, W168V, M278A, K286A, R287A, R333A, K334A, N335A, K349A, K350A, K368A, K369A, and D416N and/or one or more of E284A, K286A, R287A, N310A, R333A, K334A, R336A, K349A, K350A, K368A, and K369A and/or one R336A.

[0196] In embodiments, there is provided a method for treating a disease or disorder ex vivo, comprising contacting a cell with the composition comprising a transposase enzyme (e.g. an MLT transposase) having an amino acid sequence of SEQ ID NO: 2 and a substitution at position S2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto or comprising a transposase enzyme (e.g. an MLT transposase) having a nucleotide sequence having a nucleotide sequence of SEQ ID NO: 3, or the nucleotide sequence having at least about 80%, at least about 90%, or at least about 93%, or at least about 95%, or at least about 98% identity thereto.

[0197] In embodiments, there is provided a method for treating a disease or disorder in vivo, comprising administering the composition comprising a transposase enzyme (e.g. an MLT transposase) having an amino acid sequence of SEQ ID NO: 2 and a substitution at position S2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, or comprising a transposase enzyme (e.g. an MLT transposase) having a nucleotide sequence having a nucleotide sequence of SEQ ID NO: 3, or the nucleotide sequence having at least about 80%, at least about 90%, or at least about 93%, or at least about 95%, or at least about 98% identity thereto, or a cell comprising the composition comprising a transposase enzyme (e.g. an MLT transposase) having an amino acid sequence of SEQ ID NO: 2 and a substitution at position S2, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto, or comprising a transposase enzyme (e.g. an MLT transposase) having a nucleotide sequence having a nucleotide sequence of SEQ ID NO: 2, or the nucleotide sequence having at least about 80%, at least about 90%, or at least about 93%, or at least about 95%, or at least about 98% identity thereto.

[0198] In embodiments, the present MLT transposase, e.g. with an amino acid sequence of SEQ ID NO: 2, or a variant thereof (and optionally one or more hyperactive mutations) demonstrates improved integration efficiency relative to piggyBac. In embodiments, the present MLT transposase of an amino acid sequence of SEQ ID NO: 2, and S8P, C13R and/or N125K, demonstrates improved integration efficiency relative to piggyBac.

[0199] In embodiments, the present MLT transposase, e.g. with an amino acid sequence of SEQ ID NO: 2, or a variant thereof (and optionally one or more hyperactive mutations) can be in the form or an RNA or DNA and have one or two N-terminus nuclear localization signal (NLS) to shuttle the protein more efficiently into the nucleus. For example, in embodiments, the present MLT transposase further comprises one, two, three, four, five, or more NLSs. Examples of NLS are provided in Kosugi et al. (J. Biol. Chem. (2009) 284:478-485; incorporated by reference herein). In a particular embodiment, the NLS comprises the consensus sequence K(K/R)X(K/R) (SEQ ID NO: 348). In an embodiment, the NLS comprises the consensus sequence (K/R)(K/R)X.sub.10-12(K/R).sub.3/5(SEQ ID NO: 349), where (K/R).sub.3/5 represents at least three of the five amino acids is either lysine or arginine. In an embodiment, the NLS comprises the c-myc NLS. In a particular embodiment, the c-myc NLS comprises the sequence PAAKRVKLD (SEQ ID NO: 350). In a particular embodiment, the NLS is the nucleoplasmin NLS. In a particular embodiment, the nucleoplasmin NLS comprises the sequence KRPAATKKAGQAKKKK (SEQ ID NO: 351). In a particular embodiment, the NLS comprises the SV40 Large T-antigen NLS. In a particular embodiment, the SV40 Large T-antigen NLS comprises the sequence PKKKRKV (SEQ ID NO: 352). In a particular embodiment, the NLS comprises three SV40 Large T-antigen NLSs (e.g., DPKKKRKVDPKKKRKVDPKKKRKV (SEQ ID NO: 353). In various embodiment, the NLS may comprise mutations/variations in the above sequences such that they contain 1 or more substitutions, additions or deletions (e.g. about 1, or about 2, or about 3, or about 4, or about 5, or about 10 substitutions, additions, or deletions).

[0200] In some embodiments, the transposase is from a LEAP-IN 1 type or LEAP-IN transposon system (Biotechnol J. 2018 October; 13(10):e1700748. doi: 10.1002/biot.201700748. Epub 2018 Jun. 11).

[0201] In some embodiments, a non-viral vector includes a LEAP-IN 1 type of LEAPIN Transposase (ATUM, Newark, Calif.). The LEAPIN Transposase system includes a transposase (e.g., a transposase mRNA) and a vector containing one or more genes of interest (transposons), selection markers, regulatory elements, insulators, etc., flanked by the transposon cognate inverted terminal ends and the transposition recognition motif (TTAT). Upon co-transfection of vector DNA and transposase mRNA, the transiently expressed enzyme catalyzes high-efficiency and precise integration of a single copy of the transposon cassette (all sequences between the terminal ends) at one or more sites across the genome of the host cell. Hottentot et al. In Genotyping: Methods and Protocols. White S J, Cantsilieris S, eds: 185-196. (New York, N.Y.: Springer): 2017. pp. 185-196. The LEAPIN Transposase generates stable transgene integrants with various advantageous characteristics, including single copy integrations at multiple genomic loci, primarily in open chromatin segments; no payload limit, so multiple independent transcriptional units may be expressed from a single construct; the integrated transgenes maintain their structural and functional integrity; and maintenance of transgene integrity ensures the desired chain ratio in every recombinant cell.

[0202] Furthermore, the LEAPIN Transposase has a self-inactivating mechanism. The 3-TRE, located within an intron of the transposase construct, spatially separates the promoter regions. Therefore, enzymatic excision of the transposon located between TTAA (SEQ ID NO: 1) sites, from the plasmid during transposition, results in the separation of the promoter from the 5' end of the LEAPIN Transposase construct. The now promoterless transposase residing in the remaining plasmid backbone is inactivated if inserted non-transpositionally into the genome, thereby reducing genotoxic effects in a host cell. This can stop any protein synthesis from the mRNA constructs that may be erroneously synthesized. Urschitz et al., Proc Natl Acad Sci USA 2010; 107:8117-22.

[0203] In some embodiments, the present dual system comprises a DNA plasmid encoding a transgene, and RNA encoding a transposase (e.g., the LEAPIN Transposase). In some embodiments, the use of mRNA that encodes a transposase can have a number of advantages over delivery of a transposase-encoding DNA molecule. See, e.g. Wilber et al. Mol Ther 2006; 13:625-30. The advantages include improved control with respect to the duration of transposase expression, minimizing persistence in the tissue, and the potential for transgene re-mobilization and re-insertion following the initial transposition event. Furthermore, the transposase-encoding RNA sequence is likely incapable of integrating into the host genome, thereby eliminating concerns about long-term transposase expression and destabilizing effects with respect to the gene of interest. Furthermore, in some embodiments, the dual plasmid DNA transposon/RNA transposase system is in the form of a lipid nanoparticle (LNP), to protect from extracellular RNA degradation, which improves the in vivo use.

[0204] In some embodiments, a transgene can be associated with various regulatory elements that are selected to ensure stable expression of a construct with the transgene. Thus, in some embodiments, a transgene can be encoded by a non-viral vector (e.g., a DNA plasmid) that can comprise one or more insulator sequences that prevent or mitigate activation or inactivation of nearby genes. The insulators flank the transposon (transgene cassette) to reduce transcriptional silencing and position effects imparted by chromosomal sequences. As an additional effect, the insulators can eliminate functional interactions of the transgene enhancer and promoter sequences with neighboring chromosomal sequences. In some embodiments, the one or more insulator sequences comprise an HS4 insulator (1.2-kb 5'-HS4 chicken .beta.-globin (cHS4) insulator element) and an D4Z4 insulator (tandem macrosatellite repeats linked to Facio-Scapulo-Humeral Dystrophy (FSHD). In some embodiments, the sequences of the HS4 insulator and the D4Z4 insulator are as described in Rival-Gervier et al. Mol Ther. 2013 August; 21(8):1536-50, which is incorporated herein by reference in its entirety.

[0205] The described method enhances enzymes capable of targeted genomic integration by transposition (e.g., without limitation, transposases) by fusing them to DNA binding TALEs or dCas9/gRNA to target integrations to GSHS, which can be in areas that have open chromatin. In embodiments, a nucleic acid encoding the enzyme (e.g., DNA) encodes the enzyme in the form of first and second portions with an intein encoded between the first and second portions, such that the first and second portions are fused into a functional enzyme upon post-translational excision of the intein from the enzyme. The described method provides reduced insertional mutagenesis or oncogenesis as compared to a method with a non-chimeric transposase. Also, in some embodiments, the method is used to treat an inherited or acquired disease in a patient in need thereof.

[0206] In embodiments, there is provided a transgenic organism that may comprise cells which have been transformed by the methods of the present disclosure. In embodiments, the organism may be a mammal or an insect. When the organism is a mammal, the organism may include, but is not limited to, a mouse, a rat, a monkey, a dog, a rabbit and the like. When the organism is an insect, the organism may include, but is not limited to, a fruit fly, a mosquito, a bollworm and the like.

[0207] The compositions can be included in a container, kit, pack, or dispenser together with instructions for administration.

[0208] Also provided herein are kits comprising: i) any of the aforementioned gene transfer constructs of this invention, and/or any of the aforementioned cells of this invention and ii) a container. In certain embodiments, the kits further comprise instructions for the use thereof. In certain embodiments, any of the aforementioned kits can further comprise a recombinant DNA construct comprising a nucleic acid sequence that encodes a transposase.

[0209] In embodiments, a composition in accordance with embodiments of the present disclosure is in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" (also referred to as an "excipient" or a "carrier") is a pharmaceutically acceptable solvent, suspending agent, stabilizing agent, or any other pharmacologically inert vehicle for delivering one or more therapeutic compounds to a subject (e.g., a mammal, such as a human, non-human primate, dog, cat, sheep, pig, horse, cow, mouse, rat, or rabbit), which is nontoxic to the cell or subject being exposed thereto at the dosages and concentrations employed. Pharmaceutically acceptable carriers can be liquid or solid, and can be selected with the planned manner of administration in mind so as to provide for the desired bulk, consistency, and other pertinent transport and chemical properties, when combined with one or more of therapeutic compounds and any other components of a given pharmaceutical composition. Typical pharmaceutically acceptable carriers that do not deleteriously react with amino acids include, by way of example and not limitation: water, saline solution, binding agents (e.g., polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose and other sugars, gelatin, or calcium sulfate), lubricants (e.g., starch, polyethylene glycol, or sodium acetate), disintegrates (e.g., starch or sodium starch glycolate), and wetting agents (e.g., sodium lauryl sulfate). Pharmaceutically acceptable carriers also include aqueous pH buffered solutions or liposomes (small vesicles composed of various types of lipids, phospholipids and/or surfactants which are useful for delivery of a drug to a mammal). Further examples of pharmaceutically acceptable carriers include buffers such as phosphate, citrate, and other organic acids, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, salt-forming counterions such as sodium, and/or nonionic surfactants such as TWEEN.TM., polyethylene glycol (PEG), and PLURONICS.TM..

[0210] Pharmaceutical compositions can be formulated by mixing one or more active agents with one or more physiologically acceptable carriers, diluents, and/or adjuvants, and optionally other agents that are usually incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A pharmaceutical composition can be formulated, e.g., in lyophilized formulations, aqueous solutions, dispersions, or solid preparations, such as tablets, dragees or capsules. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (18th ed, Mack Publishing Company, Easton, Pa. (1990)), particularly Chapter 87 by Block, Lawrence, therein. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN.TM.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies as described herein, provided that the active agent in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See, also, Baldrick, Regul Toxicol Pharmacol 32:210-218, 2000; Wang, Int J Pharm 203:1-60, 2000; Charman J Pharm Sci 89:967-978, 2000; and Powell et al. PDA J Pharm Sci Technol 52:238-311, 1998), and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.

[0211] Pharmaceutical compositions include, without limitation, solutions, emulsions, aqueous suspensions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, for example, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. Emulsions are often biphasic systems comprising of two immiscible liquid phases intimately mixed and dispersed with each other; in general, emulsions are either of the water-in-oil (w/o) or oil-in-water (o/w) variety. Emulsion formulations have been widely used for oral delivery of therapeutics due to their ease of formulation and efficacy of solubilization, absorption, and bioavailability.

[0212] Compositions and formulations can contain sterile aqueous solutions, which also can contain buffers, diluents and other suitable additives (e.g., penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers). Compositions additionally can contain other adjunct components conventionally found in pharmaceutical compositions. Thus, the compositions also can include compatible, pharmaceutically active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or additional materials useful in physically formulating various dosage forms of the compositions provided herein, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. Furthermore, the composition can be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings, and aromatic substances. When added, however, such materials should not unduly interfere with the biological activities of the polypeptide components within the compositions provided herein. The formulations can be sterilized if desired.

[0213] In some embodiments, a pharmaceutical composition including a composition as provided herein can be, at least in part, in the form of a solution or powder with or without a diluent to make an injectable suspension. The composition may include additional ingredients including, without limitation, pharmaceutically acceptable vehicles, such as saline, water, lactic acid, mannitol, or combinations thereof, for example.

[0214] Any appropriate method can be used to administer a composition as described herein to a mammal. Administration can be, for example, parenteral (e.g., by subcutaneous, intrathecal, intraventricular, intramuscular, or intraperitoneal injection, or by intravenous drip). Administration can be rapid (e.g., by injection) or can occur over a period of time (e.g., by slow infusion or administration of slow release formulations). In some embodiments, administration can be topical (e.g., transdermal, sublingual, ophthalmic, or intranasal), pulmonary (e.g., by inhalation or insufflation of powders or aerosols), or oral. In addition, a composition containing a composition as described herein can be administered prior to, after, or in lieu of surgical resection of a tumor.

[0215] This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1--Design of Chimeric Transposases with Transcription Activator-Like Effector (TALE) DNA Binding Domains (DBDs) or dCas9/gRNA that Target Human Genomic Safe Harbor Sites (GSHS)

[0216] In this example, chimeric transposases were designed using human GSHS TALE or dCas9/gRNA DBD. FIGS. 1A-1D and FIG. 2 depict representations of chimeric transposase designed using human GSHS TALE or dCas9/gRNA DBD. FIG. 1A. TALEs includes nuclear localization signals (NLS) and an activation domain (AD) to function as transcriptional activators. A central tandem repeat domain confers specific DNA-binding and host specificity. Translocation signal (TD) and four cryptic repeats required for initiation of DNA binding and for the recognition of 5'-T.sup.0 are located at the N-terminus (checkered rectangles). Each 34 amino acid (aa) long repeat in the CRD binds to one nucleotide with specificity determined mainly by aa at position 13. One sample repeat is shown below the protein scheme. Numbers 12/13 refer to aa positions within the repeat. See Jankele et al., Brief Funct Genomics 2014; 13:409-19. FIG. 1B. Repeat types are shown that have specificity for one or several nucleotides. Only bases of the DNA leading strand are shown. FIG. 1C. A chimeric transposase having a TALE DNA-binding protein fused thereto by a linker that is greater than 23 amino acids in length (top). See Hew et al., Synth Biol(Oxf) 2019; 4:ysz018. FIG. 1D. Binding of the TALE to GSHS physically sequesters the transposase to the same location and promotes transposition to the nearby TTAA (SEQ ID NO: 1) sequences near repeat variable di-residues (RVD) nucleotide sequences. All RVD are preceded by a thymine (T) to bind to the NTR shown in FIG. 1A. All of these GSHS regions are in open chromatin and are susceptible to transposase activity).

[0217] FIG. 2 is a non-limiting representation of a system in accordance with embodiments of the present disclosure comprising a nucleic acid (e.g., helper RNA) encoding an enzyme capable of targeted genomic integration by transposition and a nucleic acid encoding a transposase (donor DNA). The helper RNA is translated into a bioengineered enzyme (e.g., integrase, recombinase, or transposase) that recognizes specific ends and seamlessly inserts the donor DNA into the human genome in a site-specific manner without a footprint. The enzyme can form a dimer or a tetramer at open chromatin to insert donor DNA at TTAA (SEQ ID NO: 1) recognition sites near DNA binding regions targeted by dCas9/gRNA or TALEs. Binding of the dCas9/gRNA to TALE GSHS physically sequesters the enzyme to the same location and promotes transposition to the nearby TTAA (SEQ ID NO: 1) sequences (See FIG. 3 and FIG. 4).

[0218] FIG. 1C also illustrates (bottom) a chimeric transposase construct comprising dCas9 linked to one or more guide RNAs. An engineered chimeric transposase may include: a guide RNA (gRNA) and an inactivated Cas protein. The gRNA is a short synthetic RNA composed of a scaffold sequence necessary for Cas-binding and a user-defined-20 nucleotide spacer that defines the genomic target to be modified. Thus, the genomic target of the Cas protein is based upon the sequence present in the gRNA. FIG. 4 shows gRNA sequences that physically sequester the transposase to GSHS and promotes transposition to the nearby TTAA (SEQ ID NO: 1) sequences.

[0219] FIGS. 8A-8D depict examples of construct templates. FIG. 8A depicts a plasmid construct template that transcribes transposase RNA that is later processed with a 5'-m7G cap1 and pseudouridine substitution. Other transposases can be substituted. FIG. 8B depicts a (generic) MLT donor DNA construct template that can be used for transfer of any transgene. Other dCas9/gRNAs and transposases can be substituted.

Example 2--Characterizing Transposition Activity of M. lucifugus MLT Transposase and its Hyperactive Forms

[0220] This study, in part, aims at functionally characterizing the transposition activity of M. lucifugus (MLT) transposase, including monomer, dimer, tetramer, hyperactive, and Int-forms of MLT transposase. The MLT transposase protein with the L573del, E574del, and S2A mutations, discovered in the present disclosure, can be referred to as an engineered, corrected MLT transposase in accordance with the present disclosure.

[0221] FIGS. 5A and 5B depict hyperactive, excision positive, and integration deficient (Int-) MLT mutants from the MLT transposase DNA and MLT transposase protein. For each mutant, FIG. 5A shows nucleotide changes and corresponding amino acid changes relative to a non-mutated wild type MLT transposase, having the amino acid sequence of SEQ ID NO: 4 and that is encoded by the nucleotide sequence of SEQ ID NO: 5. FIG. 5B shows mutations in the MLT transposase backbone and various MLT mutants (1, 2, and 3).

[0222] FIG. 6A depicts the three-dimensional MLT protein structure with 100% confidence that shows DNA binding domains (in red). The three dimensional MLT protein structure is generated using Phyre.sup.2 (Protein Homology/AnalogY Recognition Engine), Kelley L A et al. Nature Protocols 10, 845-858 (2015). FIG. 6B depicts secondary structure prediction for MLT, using Phyre.sup.2.

[0223] FIG. 7 depicts an amino acid sequence alignment of piggyBac ("Trichoplusia ni") transposase to MLT ("Myotis lucifugus") transposase (two different sequences), and bat transposases Myotis myotis (four different sequences) and Pteropus vampyrus. The sequences were obtained from Jebb, et al., Nature, volume 583, pages 578-584 (2020), which is incorporated herein by reference in its entirety. In FIG. 7, the alignment, generated using SnapGene.RTM. software (from GSL Biotech), is to the consensus sequence. Amino acids that match the reference (consensus), i.e. highly conserved mammalian transposase sequences, are marked with yellow highlighting. Consensus threshold is greater than 50%.

[0224] In this example, the sequences shown in FIGS. 3, 4, and 7, or any other sequences, are used in testing varying combinations of MLT mutants, to identify candidates for targeting genomic safe harbor sites with site-specific TALEs or dCas9/gRNA. Hyperactive, excision positive, or Int-MLT mutants can be generated by synthetic DNA synthesis by substituting the mutations in FIGS. 5A and 5B in a MLT transposase described herein, e.g. a nucleotide and amino acid sequence.

[0225] In this example, a genetic assay as described, for example, in Example 8 of International Application WO2010085699, which is incorporated herein by reference in its entirety, can be used for screening for an increased frequency of Ura+ reversion. The genetic assay uses a modified version of the yeast URA3 gene as a transposon donor, for the excision of MLT in yeast (Saccharomyces cerevisiae).

Example 3--Characterizing Integration Efficiency of Piggybac, Wild-Type Mlt Transposase, and Engineered Mlt Transposase of the Disclosure

[0226] A goal of this study was to assess integration efficiency of known hyperactive piggyBac transposases, including those from published sources, and of an engineered MLT transposase in accordance with the present disclosure. The wild type Myotis Lucifugus transposase (MLT) sequence was described in a WO2010/085699 publication (of PCT/US2010/021871) and in Mitra et al., PNAS 2013; 110:234. The nucleotide sequence of a transposase from Mitra et al. (2013) has 77% sequence identity to the MLT transposase of the present disclosure (referred to as "MLT") that has the nucleotide sequence of SEQ ID NO: 3. See FIG. 10, which depicts a nucleotide sequence alignment of hyperactive MLT (human codon-optimized for RNA) and published sequence from Mitra et al. (2013) (Identity 77.67%, gaps 1.44%). The nucleotide sequence of MLT and the nucleotide sequence from WO2010085699 have 73.68%, identity (gaps 1.16%), as shown in FIG. 11 containing their alignment.

[0227] Furthermore, the end sequences of the engineered MLT transposase of the present disclosure are different than those referenced by Mitra et al. (2013) (see Ray et al., Genome Res 2008; 18:717). FIG. 14 and FIG. 15 show left and right terminal ends of the engineered MLT transposase, compared to left and right terminal ends of the published sequence from Ray et al., 2018.

[0228] FIG. 12 illustrates an amino acid alignment of the engineered hyperactive MLT transposase (L573del/E574del/S2A, with S8P, C13R, and N125K mutations, "MLT") and a published sequence by Mitra et al. (the differences between the amino acid sequences are underlined and bolded). As shown in FIG. 12, the amino acid sequence from Mitra et al. contained two extra C-terminal amino acids relative to the MLT transposase of the present disclosure.

[0229] FIG. 13 illustrates an amino acid alignment of the engineered, hyperactive MLT transposase (L573del/E574del/S2A, with S8P and C13R mutations, "MLT") and a published sequence from WO2010085699 (the differences between the amino acid sequences are underlined and bolded). The sequence from the WO2010085699 publication had multiple amino acid residue changes compared to the amino acid sequence of the MLT transposase of the present disclosure. WO2010085699 described hyperactive transposase enzymes comprising amino acid changes in the sequence as shown in FIG. 13, the amino acid changes selected from A14V, D475G, P491Q, A561T, T546T, T300A, T294A, A520T, G239S, S5P, S8F, S54N, D9N, D9G, I345V, M481V, E11G, K130T, G9G, R427H, S8P, S36G, D10G, S36G and silent.

[0230] FIGS. 9A and 9B are bar charts illustrating results of assessment of integration efficiency of the engineered MLT transposase of the present disclosure and other (known) transposases. FIG. 9A illustrates integration efficiency of a hyperactive piggyBac transposase from Yusa et al. PNAS 2010; 108:1531-1536 (see FIGS. 16A, 16B, 16C, and 16D), used with a piggyBac donor (CMV-GFP, see FIG. 15), versus the engineered MLT transposase of the present disclosure (S8P/C13R/S2A/L573del/E574del MLT) used with an MLT donor (CMV-GFP, see FIG. 16 that shows an example of a DNA donor construct template).

[0231] The hyperactive piggyBac amino acid sequence used in the study show in FIG. 9A and FIG. 9B (from Yusa et al. (2010), with I30V, S103P, G165S, M282V, S509G, N538K, and N571S mutations, shown bolded and underlined) is as follows:

TABLE-US-00015 (SEQ ID NO: 17) 1 MGSSLDDEHI LSALLQSDDE LVGEDSDSEV SDHVSEDDVQ SDTEEAFIDE VHEVQPTSSG 61 SEILDEQNVI EQPGSSLASN RILTLPQRTI RGKNKHCWST SKPTRRSRVS ALNIVRSQRG 121 PTRMCRNIYD PLLCFKLFFT DEIISEIVKW TNAEISLKRR ESMTSATFRD TNEDEIYAFF 181 GILVMTAVRK DNHMSTDDLF DRSLSMVYVS VMSRDRFDFL IRCLRMDDKS IRPTLRENDV 241 FTPVRKIWDL FIHQCIQNYT PGAHLTIDEQ LLGFRGRCPF RVYIPNKPSK YGIKILMMCD 301 SGTKYMINGM PYLGRGTQTN GVPLGEYYVK ELSKPVHGSC RNITCDNWFT SIPLAKNLLQ 361 EPYKLTIVGT VRSNKREIPE VLKNSRSRPV GTSMFCFDGP LTLVSYKPKP AKMVYLLSSC 421 DEDASINEST GKPQMVMYYN QTKGGVDTLD QMCSVMTCSR KTNRWPMALL YGMINIACIN 481 SFIIYSHNVS SKGEKVQSRK KFMRNLYMGL TSSFMRKRLE APTLKRYLRD NISNILPKEV 541 PGTSDDSTEE PVMKKRTYCT YCPSKIRRKA SASCKKCKKV ICREHNIDMC QSCF

[0232] The hyperactive piggyBac nucleotide sequence used in the study show in FIG. 9A and FIG. 9B (mutated codons underlined and bolded) is as follows:

TABLE-US-00016 (SEQ ID NO: 18) 1 ATGGGCAGCA GCCTGGACGA CGAGCACATC CTGAGCGCCC TGCTGCAGAG CGACGACGAG 61 CTGGTCGGCG AGGACAGCGA CAGCGAGGTG AGCGACCACG TGAGCGAGGA CGACGTGCAG 121 TCCGACACCG AGGAGGCCTT CATCGACGAG GTGCACGAGG TGCAGCCTAC CAGCAGCGGC 181 TCCGAGATCC TGGACGAGCA GAACGTGATC GAGCAGCCCG GCAGCTCCCT GGCCAGCAAC 241 AGGATCCTGA CCCTGCCCCA GAGGACCATC AGGGGCAAGA ACAAGCACTG CTGGTCCACC 301 TCCAAGCCCA CCAGGCGGAG CAGGGTGTCC GCCCTGAACA TCGTGAGAAG CCAGAGGGGC 361 CCCACCAGGA TGTGCAGGAA CATCTACGAC CCCCTGCTGT GCTTCAAGCT GTTCTTCACC 421 GACGAGATCA TCAGCGAGAT CGTGAAGTGG ACCAACGCCG AGATCAGCCT GAAGAGGCGG 481 GAGAGCATGA CCTCCGCCAC CTTCAGGGAC ACCAACGAGG ACGAGATCTA CGCCTTCTTC 541 GGCATCCTGG TGATGACCGC CGTGAGGAAG GACAACCACA TGAGCACCGA CGACCTGTTC 601 GACAGATCCC TGAGCATGGT GTACGTGAGC GTGATGAGCA GGGACAGATT CGACTTCCTG 661 ATCAGATGCC TGAGGATGGA CGACAAGAGC ATCAGGCCCA CCCTGCGGGA GAACGACGTG 721 TTCACCCCCG TGAGAAAGAT CTGGGACCTG TTCATCCACC AGTGCATCCA GAACTACACC 781 CCTGGCGCCC ACCTGACCAT CGACGAGCAG CTGCTGGGCT TCAGGGGCAG GTGCCCCTTC 841 AGGGTCTATA TCCCCAACAA GCCCAGCAAG TACGGCATCA AGATCCTGAT GATGTGCGAC 901 AGCGGCACCA AGTACATGAT CAACGGCATG CCCTACCTGG GCAGGGGCAC CCAGACCAAC 961 GGCGTGCCCC TGGGCGAGTA CTACGTGAAG GAGCTGTCCA AGCCCGTCCA CGGCAGCTGC 1021 AGAAACATCA CCTGCGACAA CTGGTTCACC AGCATCCCCC TGGCCAAGAA CCTGCTGCAG 1081 GAGCCCTACA AGCTGACCAT CGTGGGCACC GTGAGAAGCA ACAAGAGAGA GATCCCCGAG 1141 GTCCTGAAGA ACAGCAGGTC CAGGCCCGTG GGCACCAGCA TGTTCTGCTT CGACGGCCCC 1201 CTGACCCTGG TGTCCTACAA GCCCAAGCCC GCCAAGATGG TGTACCTGCT GTCCAGCTGC 1261 GACGAGGACG CCAGCATCAA CGAGAGCACC GGCAAGCCCC AGATGGTGAT GTACTACAAC 1321 CAGACCAAGG GCGGCGTGGA CACCCTGGAC CAGATGTGCA GCGTGATGAC CTGCAGCAGA 1381 AAGACCAACA GGTGGCCCAT GGCCCTGCTG TACGGCATGA TCAACATCGC CTGCATCAAC 1441 AGCTTCATCA TCTACAGCCA CAACGTGAGC AGCAAGGGCG AGAAGGTGCA GAGCCGGAAA 1501 AAGTTCATGC GGAACCTGTA CATGGGCCTG ACCTCCAGCT TCATGAGGAA GAGGCTGGAG 1561 GCCCCCACCC TGAAGAGATA CCTGAGGGAC AACATCAGCA ACATCCTGCC CAAAGAGGTG 1621 CCCGGCACCA GCGACGACAG CACCGAGGAG CCCGTGATGA AGAAGAGGAC CTACTGCACC 1681 TACTGTCCCA GCAAGATCAG AAGAAAGGCC AGCGCCAGCT GCAAGAAGTG TAAGAAGGTC 1741 ATCTGCCGGG AGCACAACAT CGACATGTGC CAGAGCTGTT TC

[0233] The hyperactive piggyBac left ITR nucleotide sequence used in the study show in FIG. 9A and FIG. 9B (205 bp) is as follows:

TABLE-US-00017 (SEQ ID NO: 19) 1 TTAACCCTAG AAAGATAATC ATATTGTGAC GTACGTTAAA GATAATCATG CGTAAAATTG 61 ACGCATGTGT TTTATCGGTC TGTATATCGA GGTTTATTTA TTAATTTGAA TAGATATTAA 121 GTTTTATTAT ATTTACACTT ACATACTAAT AATAAATTCA ACAAACAATT TATTTATGTT 181 TATTTATTTA TTAAAAAAAA ACAAA

[0234] The hyperactive piggyBac right ITR nucleotide sequence used in the study show in FIG. 9A and FIG. 9B (310 bp) is as follows:

TABLE-US-00018 (SEQ ID NO: 20) 1 ATCTATAACA AGAAAATATA TATATAATAA GTTATCACGT AAGTAGAACA TGAAATAACA 61 ATATAATTAT CGTATGAGTT AAATCTTAAA AGTCACGTAA AAGATAATCA TGCGTCATTT 121 TGACTCACGC GGTCGTTATA GTTCAAAATC AGTGACACTT ACCGCATTGA CAAGCACGCC 181 TCACGGGAGC TCCAAGCGGC GACTGAGATG TCCTAAATGC ACAGCGACGG ATTCGCGCTA 241 TTTAGAAAGA GAGAGCAATA TTTCAAGAAT GCATGCGTCA ATTTTACGCA GACTATCTTT 301 CTAGGGTTAA

[0235] As shown in FIG. 9A, the MLT transposase of the present disclosure had a greater integration efficiency that the transposase from Yusa et al. (2010). The inventors have discovered that a transposase sequence without the last two amino acids (L573del, E574del) has a greater efficiency than a transposase with those terminal amino acids present.

[0236] FIG. 9B illustrates an integration efficiency of the engineered MLT of the present disclosure, compared to integration efficiencies of piggyBac mutants. FIG. 9B shows percent of integration efficiency for a) hyperactive piggyBac (from Yusa et al. (2010), see SEQ ID NOs: 17, 18, 19, and 20)+piggyBac donor (see FIG. 16); b) hyperactive piggyBac donor only (see FIG. 16); c) MLT donor only (see FIG. 16); d) wild-type MLT+MLT donor; e) MLT N125K+MLT donor; f) MLT S8P/C13R+MLT donor; g) engineered MLT of the present disclosure (MLT S8P/C13R/L573del/E574del)+MLT donor; and h) hyperactive piggyBac dimer+piggyBac donor. The hyperactive piggyBac donor (b) and the MLT donor (c) were used as controls. As shown in FIG. 9A and FIG. 9B, the engineered MLT of the present disclosure has an integration efficiency comparable to the hyperactive piggyBac+piggyBac donor system.

Example 4--In Vitro Analysis of Hyperactive MLT Transposase Variants in HeLa and HEK293 Cells

[0237] This study showed a discovery of novel mutations in a mammalian transposase in accordance with the present disclosure (an MLT transposase), to improve its excision capabilities (Exc+) by evaluating hyperactive mutants for their relative integration efficiency. This study details the analysis of hyperactive MLT transposase mutants in HeLa and HEK293 cells.

DNAs for the Mammalian Cell Integration Assays.

[0238] A two-plasmid transposition assay, using a donor plasmid including a transposon carrying a GFP gene and blasticidin resistance (BsdR) cassette and a helper plasmid expressing the transposase under a cytomegalovirus (CMV) promoter to measure transposition. The insect piggyBac donor plasmid contained GFP and BsdR cassettes driven by a CMV promoter, flanked by end sequences in a ZeoCassette.TM. Vector (pCMV/Zeo) (Thermo Fisher Scientific) backbone. The insect piggyBac helper plasmid contained the piggyBac ORF cloned into pcDNA3.1 myc His A-His (Invitrogen). For the MLT donor plasmid, the GFP-Bsd cassette from the insect piggyBac mammalian donor pCMV/miniPB-GFP-Bsd was PCR amplified using specific primers. The fragment was digested and cloned into the MLT donor plasmid. In the MLT mammalian helper plasmid, the enzyme was tagged with a HA tag. The MLT ORF was PCR amplified from plasmid--with a primer from the 5' end of the gene and a primer from the 3' end of the gene. The PCR product was digested and cloned into the plasmid. Various mutations in the putative catalytic domains were synthesized and evaluated.

Mammalian Cell Integration Assay.

[0239] HeLa cells were grown in DMEM+10% FBS+penicillin-streptomycin. HeLa cells (2.times.10.sup.5) were transfected with donor (294 nM) and helper (42 nM) plasmids with FuGENE-HD (Roche) in OPTI-MEM media (Life Technologies) according to the manufacturer's protocol. Cells transfected with donor plasmid and empty pCDNA3.1/myc-His A were the non-transposase control. After 46 h of transfection, cells were trypsinized and serially diluted in the appropriate DMEM as described above+blasticidin (3.5 .mu.g/mL). Fresh media with antibiotics were administered every 24 h and continued for 21 d. After 21 days, cells were fixed with 4% paraformaldehyde and stained with 0.2% methylene blue, and blue colonies were counted.

Results

[0240] FIGS. 17A and 17B show results of functional assessment of the hyperactive MLT transposase mutants in HeLa cell. FIG. 17A shows that mammalian transposase (Ts) variants S8P, C13R, N125K and S8P/C13R have higher excision and integration frequency than the native enzyme. FIG. 17B shows functional transgene expression in HeLa cells transfected with a donor neomycin transgene, 1:20 serial dilutions. The mammalian MLT transposase variant S8P/C13R showed comparable relative integration to the insect piggyBac in HeLa cells.

[0241] FIG. 18 shows relative integration frequency of MLT transposase hyperactive mutants in HEK293 cells. The double mutant A/C shows that highest integration efficiency was observed in HEK293 cells.

[0242] The MLT transposase transposed successfully in human cultured HeLa and HEK293. A two-plasmid co-transfection assay was used in which a donor plasmid carried a transposon comprising an antibiotic resistance marker and a helper plasmid expressing the transposase, measuring the transposase-dependent chromosomal integration of the transposon antibiotic marker. It was found that the relative frequency of integration using the hyperactive MLT transposase was comparable to the insect wild type and hyperactive piggyBac in HeLa cells (FIGS. 17A and 17B) but about 50% in HEK293 cells (FIG. 18).

[0243] In the present study, the relative integration efficiencies of mammalian MLT transposase hyperactive variants D and A/C were comparable to insect piggyBac in HeLa cells. These variants also showed integration hyperactivity in HEK293 cells.

Example 5--MLT Transposase Protein Isolation and Purification

[0244] A goal of this study was to isolate an MLT transposase protein.

Protein Expression and Purification

[0245] The gene for a full-length MLT transposase of the present disclosure was codon-optimized for mammalian expression and cloned into the pD2610 expression vector between BamHI and Kpnl restriction sites, downstream of an N-terminal maltose-binding protein (MBP) tag followed by a TEV protease cleavage site. The plasmid pD2610-MPB-MLT transposase was transfected into 500 ml EXPI293F cells (Thermo Fisher Scientific) for transient protein expression using a standard PEI transfection protocol. The transfected cells were supplied with 1 L Expi293 expression medium after 24 h. Cells were harvested 3 days after transfection at 300.times.g and stored at -80.degree. C. Cells expressing MBP-tagged MLT transposase were resuspended in lysis buffer containing 25 mM Tris-CI, pH 7.5, 500 mM NaCl, 1 mM TCEP, and protease inhibitor cocktail (Roche). The cells were lysed by three cycles of sonication. Cell lysates were centrifuged at .about.95,000.times.g for 30 min at 4.degree. C. (Beckman Coulter Optima L-100 XP Ultracentrifuge, Type 45 Ti rotor). The supernatant was filtered and mixed with 10 ml amylose resin (New England BioLabs) equilibrated with lysis buffer. After one hour of continual rotation, the mixture was loaded onto a gravity flow column and washed with 100 ml lysis buffer. The protein was eluted with 50 ml elution buffer (25 mM Tris-CI, pH 7.5, 500 mM NaCl, 10 mM maltose, 1 mM TCEP, and protease inhibitor cocktail). The eluate was incubated with TEV protease and dialyzed against dialysis buffer (50 mM Tris-CI, pH 7.5, 500 mM NaCl, and 1 mM TCEP) for 16-20 h at 4.degree. C. The cleaved MBP tag and the MLT transposase were separated heparin elution. A sample volume onto the Superdex 200 column connected to an AKTA system equipped with an autosampler and installed with the UNICORN system control software. Eluted protein was monitored at 260 nm and 280 nm. For data analysis, the QtiPlot software was used. Purified MLT transposase was stored at -80.degree. C. The yield was 0.45 mL at 2.2 mg/mL or about 1 mg/L cell culture.

Results

[0246] FIGS. 19A and 19B show images of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. FIG. 19A shows analysis of purified MBP-MLT transposase fusion protein by an amylose-resin column. A major protein band of 100+ kDa was identified by SDS-PAGE after purification of the expressed protein (MBP-MLT transposase) from the supernatant of the sonicated bacteria on a column of amylose resin. In FIG. 19B, shows a 67.5 kDa MLT transposase-specific band was shown after overnight cleavage of the MBP tag by TEV protease and heparin elution.

[0247] Affinity chromatography of the MBP MLT transposase fusion protein was performed with amylose agarose resin, followed by a step elution. The loaded samples, flow through, washes, and eluted proteins were analyzed by SDS-PAGE to show the pool peak fractions containing the MBP-MLT transposase purified protein (FIG. 19A). The MLT transposase was separated from the MBP tag by heparin elution with a size of 66-68 kD by SDS PAGE (FIG. 19B).

[0248] FIG. 20 shows Superdex size exclusion chromatography. A sample volume of purified MLT transposase was loaded onto the Superdex 200 column. The eluted protein peaks at 260 nm and 280 nm suggest a dimer formation. Thus, the chromatographic profile indicates that the MLT transposase exists as a dimer (FIG. 20).

[0249] This study demonstrated that DNA binding proteins can be produced as fusion proteins to enable more specific purification, but their ability to bind DNA also enable affinity purification using heparin as a ligand. This study also showed that the MLT transposase of the present disclosure is a DNA binding protein with a molecular weight of approximately 67.5 kD that exists as a dimer.

Example 6--Assessing Integration Profile Differences Between MLT Transposase and PiggyBac Transposase

[0250] An objective of this study was to assess the integration pattern differences between the insect derived PiggyBac (PB) transposase and the non-specific, mammal-derived MLT transposase of the present disclosure. The comparison involved comparison of molecular sizes, protein lengths, recognition ends, integration in RefSeq genes, .+-.5 kb transcription start site, 5 kb from CpG islands, and immunogenicity. An example of a DNA MLT Helper construct is shown in FIG. 21.

[0251] In general, the MLT transposase and the PiggyBac transposase when delivered as DNA are similar in the integration and molecular characteristics, as shown in Table 1.

TABLE-US-00019 TABLE 1 Comparison of certain properties of piggyBac and MLT DNA transposases. Characteristics piggyBac MLT Species of origin Cabbage looper moth Mammalian Molecular size ~2.5 kb in length 1.9 kb in length Protein length 594 amino acids 571 amino acids Recognition Ends ITRs: 35 bp, 63 bp Ends: 157 bp; 212 bp Integration in RefSeq ~55% ~40% genes (random 34%) .+-.5 kb transcription start ~20% ~10% site (random 0.04%) .+-.5 kb from CpG islands ~20% ~10% immunogenicity Unknown (insect Likely low (mammal protein) protein)

[0252] The comparisons made herein showed that the MLT and piggyBac when delivered as DNA have similar characterics. The comparisons in Table 1 also show that the MLT transposase is safer than the piggyBac transposase and is thus less likely to cause undesired disruption or activation of genes during integration.

Example 7--Comparison of Integration Efficiency of Hyperactive Mlt Transposase and Hyperactive Piggybac

[0253] An objective of this study was to assess the integration efficiency differences of the most hyperactive form of insect derived transposase PiggyBac (PB) (I30V/G165S, S103P, M282V, S509G/N570S, N538K) and the hyperactive, non-specific mammal-derived transposase, MLT transposase in accordance with the present disclosure (with S8P/C13R mutations) (referred to as hypMLT herein).

[0254] Hyperactive piggyBac (hypPB) transposase enzyme [containing seven mutations--I30V/G165S, S103P, M282V, S509G/N570S, N538K-(7pB)] is used for gene transfer in human cells in vitro and to somatic cells in mice in vivo. Despite a protein level expression similar to that of a native PB, hypPB significantly increased the gene transfer efficiency of a neomycin resistance cassette transposon in both HEK293 and HeLa cultured human cells. Native PB and SB100X, the most active transposase of the Sleeping Beauty transposon system, exhibited similar transposition efficiency in cultured human cell lines. When delivered to primary human T cells ex vivo, hypPB increased gene delivery two- to threefold compared with piggyBac and SB100X. hypPB was compared with native PB and SB100X in vivo in mice using hydrodynamic tail-vein injection of a limiting dose of transposase DNA combined with luciferase reporter transposons. Transgene expression was monitored for up to 6 months and observed approximately 10-fold greater long-term gene expression in mice injected with a hypPB, compared with mice injected with native PB or SB100X.

Methodology

[0255] HEK293 cells were plated in 12-well size plates the day before transfection. [0256] The day of the transfection, the media was exchanged 1 hour and 30 min before the transfection was performed. [0257] The X-tremeGENE.TM. 9 DNA Transfection Reagent was used, in accordance with manufacturer's protocol (Sigma-Aldrich). [0258] In duplicate, a donor plasmid containing GFP and a helper plasmid (600 ng each), were co-transfected. The donor DNA was mixed for each duplicate transfection, and 1200 ng of helper RNA (transposase) was mixed with 1200 ng of donor DNA for 2400 ng total. A 3:1 ratio of X-tremeGENE.TM. 9 DNA Transfection Reagent was used; therefore, each duplicate had 2400 ng of DNA and used 7.2 ul of the X-tremeGENE.TM. 9 DNA Transfection Reagent. [0259] Two different donor plasmids, one for hypPB and one for hypMLT, were used. All PB transposases were mixed with the PB donor but not with an MLT donor. [0260] 48 hours after the transfection, the cells were analyzed by flow cytometry, and percent (%) of GFP expressing cells was counted, to measure transient transfection efficiency. The cells were gated to distinguish them from the debris, and 20,000 cells were counted each. GFP gating was liberal, such that even GFP-dim cells were counted as GFP-positive (GFP+) cells. [0261] The cells were cultured for 15-20 days without an antibiotic. The cells were passaged 2/3 times per week. [0262] Flow cytometry was used to percent (%) of GFP-expressing cells, to measure integration efficiency at 2 weeks (80,000 cells were counted). Gating was conservative, such that a gate was drawn around the obvious bright population and excluded very dim cells. [0263] The final integration efficiency was calculated by dividing 2-week % GFP cells by 48 hours.

Results

[0264] FIG. 22A shows % of integration activity for no MLT, MLT-dCas9, MLT-dCas12j, hyperacive piggyBac-dCas12j, hyperacive piggyBac-dCas9, hyperacive piggyBac, and MLT. FIG. 22B shows % of excision activity for no MLT, MLT-Intein-N-terminus, MLT1, and MLT2. FIG. 22C shows % of integration activity for no MLT, MLT-Intein-N-terminus, MLT1, and MLT2. FIG. 22D shows % of excision activity for no MLT, MLT-Cas12j, MLT-Cas9, MLT-Intein-N-terminus Cas9, MLT-Intein-N-terminus, MLT-Intein-N-terminus TALE, MLT-TALE10, and MLT.

[0265] FIG. 22A shows integration efficiency of a hyperactive form of piggyBac (hypPB) compared to MLT transposase (MLT2). The integration efficiency for the hyperactive MLT transposase (about 28%) was greater than the integration efficiency for the hyperactive form of piggyBac (about 24%) that is typically used for cell and gene therapy. Integration efficiency was reduced by the addition of dead Cas (dCas) binders. The addition of reduced excision activity from 30% to 18% (FIG. 22D). The addition of dCas to MLT reduced excision activity to 8% (FIG. 22D).

Example 8--In Vitro Analysis of Human ROSA26 Genomic Safe Harbor Site Targeting

[0266] A goal of this study was to assess efficacy of RNA-guided transposition to direct a transposase to the human safe harbor site, ROSA26.

[0267] In the present study, a panel of RNA-guided transposase vectors containing mutations in the native piggyBac DBD was studied for their ability to target the human ROSA26 safe harbor site.

Plasmid Development

[0268] Representations of targeting piggyBac plasmids are shown in FIGS. 23A, 23B, 23C, 23D, and 23E. FIG. 23A shows a dCas9-PB-4 guide helper--catalytically inactive dCas9 fused to the transposase (piggyBac) via a flexible linker and placed under control the CAG promoter, with guide RNA. FIG. 23B shows the shows a dCas9-PB-4 guide helper, devoid of guide RNA. FIG. 23C shows a control PB (piggyBac) helper, devoid of the dCas9 DNA-binding protein. FIG. 23D shows a non-insertional control helper (dCas9 under control the CAG promoter) devoid of the transposase (DPB). FIG. 23E shows a donor plasmid including the TurboGFP internal ribosomal entry site (IRES) neomycin transgene under the CMV promoter and flanked by the transposon terminal repeat elements (TREs).

[0269] FIG. 23F is a non-limiting schematic of a model for improvement of specificity by disruption of a piggyBac transposase DNA binding domain DBD. The native PB transposase retains full DNA-binding capability and can either integrate following dCas9 targeting (on-target), or integrate following binding to off-target sequences without dCas9 targeting (off-target). Similar to PB, the H2 and H3 mutant transposase integration deficient variants (Int-) can integrate following dCas9 targeting (on-target). However, off-target binding of the transposase is inhibited due to mutations in the DNA binding domain. FIG. 23F illustrates a rationale for using Int-transposase mutants.

[0270] FIG. 23H depicts a chimeric MLT transposase construct attached to a TALE DNA binder. Other TALEs and transposases can be substituted to target specific genomic sites.

[0271] FIG. 23G depicts a MLT transposase attached to dCas by using NpuN:

TABLE-US-00020 (SEQ ID NO: 423) ggcggatctggcggtagtgctgagtattgtctgagttacgaaacgga aatactcacggttgagtatgggcttcttccaattggcaaaatcgttg aaaagcgcatagagtgtacggtgtattccgtcgataacaacggtaat atctacacccagccggtagctcagtggcacgaccgaggcgaacagga agtgttcgagtattgcttggaagatggctcccttatccgcgccacta aagaccataagtttatgacggttgacgggcagatgctgcctatagac gaaatatttgagagagagctggacttgatgagagtcgataatctgcc aaat

TABLE-US-00021 (SEQ ID NO: 424) ggcggatctggcggtagtgggggttccggatccataaagatagcta ctaggaaatatcttggcaaacaaaacgtctatgacataggagttga gcgagatcacaattttgctttgaagaatgggttcatcgcgtctaat tgcttcaacgctagcggcgggtcaggaggctctggtggaagc

intein protein splicing. Other dCas can be substituted to target specific genomic sites.

[0272] The SpCas9-HF1 gene was mutated at the D10A and H840A residues to inactivate the catalytic domain and generate dCas9. The dCas9-PB helper plasmid was generated using Gibson assembly by fusing the a transposase gene (PB) to the dCas9 DNA-binding protein using a flexible linker described previously. The fusion protein was placed under the CAG (cytomegalovirus (CMV) immediate early enhancer, chicken b-actin promoter and b-globin intron) promoter. Two mutant transposase helper plasmids containing codon changes in the DBD were generated using Gibson assembly. First, the transposase was human codon-optimized and synthesized by Genscript. Next, mutations R372A and D450N were introduced to generate the dCas9-H2 helper plasmid and a third K375A mutation was introduced to generate the dCas9-H3 helper plasmid. Four gRNAs were appended to the helper plasmid backbone using Golden Gate. Briefly, single stranded oligos containing the guide sequence were annealed and ligated into Bbsl linearized expression plasmids containing either the hU6, mU6, H1 or 7SK promoter. One of each of the four resulting guide expression plasmids were first digested with BsmBI and then assembled into a single BsmBI-linearized helper plasmid in a single step. For experiments requiring eight guides, two plasmids each containing four guides were co-transfected in equal amounts. Negative control helper plasmids lacked gRNAs. Control helper plasmids that contained either the PB, H2 or H3 transposase but lacking a DBD were also generated using Gibson assembly. To generate the non-integrating DPB control, the entire piggyBac coding sequence was removed from the dCas9-PB helper plasmid using Gibson assembly. To generate the donor plasmid, Gateway cloning (Thermo Fisher) was used to recombine a pENTR plasmid featuring the CMV promoter driving TurboGFP, internal ribosome entry site (IRES) and neomycin (GIN) gene with a pDONR plasmid containing piggyBac terminal repeat elements (TREs) flanking the transgene.

Cell Transfections

[0273] Human embryonic kidney (HEK293) cells were maintained incomplete Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% heat inactivated fetal bovine serum. Prior to transfection, 4.times.10.sup.5 cells per well were seeded in 6-well plates. Cells at .about.80% confluency were transfected with 2 ug of plasmid DNA using X-tremeGENE 9 (Sigma-Aldrich). Twenty-four hours after transfection, cells were resuspended and 10% of cells were removed for flow cytometry analysis to measure transfection efficiency. Forty-eight hours after transfection, 90% of the cells were transferred to a T75 flask and cultured for 3 weeks under 200 mg/ml G418 at which point the cells were pelleted for lysis and genomic polymerase chain reaction (PCR) analysis. The remaining 10% of cells in the 6-well dish were cultured without antibiotic for 3 weeks and analyzed by flow cytometry to measure stable insertion efficiency. For single-cell isolation, two dCas9-H2-8 guide transfections were repeated. The G418-selected polyclonal populations were each plated into a 96-well poly-D-lysine coated plate (BD Biosciences) resulting in an average of 50 colonies per well. After wells became greater than 40% confluent, media was aspirated, and the cells were manually resuspended in 30 ml of phosphate-buffered saline. A volume of 20 ml of the resuspension was removed and mixed with 30 ml of the DirectPCR Lysis Reagent (Viagen Biotech) for analysis. The remaining cells were cultured further. Two wells identified to contain targeted clones by genomic PCR were expanded and single-cell sorted using serial dilution. Wells were visually monitored until 157 single-cell expansions were obtained. Clonally expanded cells were subsequently resuspended by manual pipetting and lysed for analysis. Positive clonal lines, containing targeted insertions to human ROSA26 (FIG. 24A) were expanded for flow cytometry analysis to detect potential silencing of the transgene.

[0274] Flow Cytometry

[0275] Green fluorescent protein (GFP) expression of 20,000 live cells from ROSA26-targeted single-cell expansions was analyzed using a FACSAria III cytometer (BD Biosciences) after 13 weeks of culture, following transfection with dCas9-H2-8guide.

Colony Count Assay

[0276] In order to determine the number of transposons present in human ROSA26-targeted single clones, a copy number assay was performed by TaqMan quantitative PCR to estimate the number of neomycin genes present in the genome. The human RNase P gene was used to normalize the total genomes per sample. Templates included: genomic DNA from clonal lines, negative control untransfected human genomic DNA and reference control genomic DNA from a clonal cell line with a single neomycin gene insertion. Quantitative PCR using the QuantStudio 12K Flex thermocycler (Applied Biosystems) was performed using the TaqPath ProAmp Master Mix reagent (Thermo Fisher) according to the manufacturer's instructions. Primers and probes were included in the TaqMan Copy Number Reference Assay for human RNase P and the TaqMan NeoR Assay ID:Mr00299300_cn (Thermo Fisher). CopyCaller Software v2.1 was used to predict the number of insertions for each sample.

T7 Endonuclease I Assay

[0277] In 12-well plates, HEK293 cells at 80% confluency in DMEM supplemented with 10% heat inactivated fetal bovine serum, were co-transfected with 500 ng of SpCas9-HF1 expression plasmid and 500 ng of one of eight ROSA26 directed gRNA or negative control gRNA expression plasmids, using X-tremeGENE 9 (Sigma-Aldrich). Seventy-two hours later, cells were pelleted and lysed using DirectPCR Cell lysis buffer (Viagen Biotech). Genomic PCR using the KOD Xtreme Hot Start DNA Polymerase (Novagen) was performed using primers designed to flank all eight guide binding sites. Products were purified with the PureLink PCR Micro Kit (Invitrogen) and melted and reannealed to form heteroduplexes. For each sample, identical incubations with or without T7 endonuclease I (T7E1) (New England Biolabs) were performed to cut DNA containing mismatched sequences. Products were separated on a 2% gel for gel imaging. A 2100 Bioanalyzer (Agilent) was used to measure the concentration of products obtained by the T7E1 assay. The fraction of cleaved products was calculated by dividing the total pg/II of the two expected cleavage products by the total pg/II of the two expected cleavage products and uncleaved product. Percent of indel occurrence was calculated.

Nested PCR

[0278] HEK293 cells were plated in 12-well size plates the day before transfection. The day of the transfection the media is exchanged 1.5 hr before the transfection is performed. The present experiments used X-tremeGENE.TM. 9 DNA Transfection Reagent and manufacturer's protocol (Sigma-Aldrich).

[0279] In triplicate transfections, a donor plasmid containing GFP and neomycin, a helper plasmid with a DBD fused to either pB or MLT transposase, and a guide RNA expression plasmid or combination of plasmids were co-transfected. The DNA was mixed for each triplicate transfection, i.e. 1500 ng of helper plasmid was mixed with 1500 ng of donor plasmid and 600 ng of guide RNA, with a total of 3600 ng. A 3:1 ratio of XtremeGene9 reagent was used, such that each triplicate transfection had 3600 ng of DNA and used 10.8 ul of reagent. 48 hours after transfection, the cells are resuspended and plated into a T75 flask. 72 hours after transfection, the media was changed from a normal media to a G418-containing media. The cells in the G418-containing media were cultured for 3 weeks, and the cells were then pelleted.

[0280] Cell lysis and Proteinase K treatment was then performed (DirectPCR Lysis Reagent, Viagen Biotech), to prepare genomic DNA for template for PCR.

[0281] Primary PCR was performed using half the primers extending from the genome and half the primers extending from the transposon insert (FIG. 24B). FIG. 24B depicts a nested PCR strategy to detect the insertion of a donor MLT at a specific TTAA (SEQ ID NO: 1) site in human ROSA26 locus using MLT helper with Cas9 and two different sets of gRNA (Set 1: AATCGAGAAGCGACTCGACA (SEQ ID NO: 425), TGCCCTGCAGGGGAGTGAGC (SEQ ID NO: 426); Set 2: GAAGCGACTCGACATGGAGG (SEQ ID NO: 427), CCTGCAGGGGAGTGAGCAGC (SEQ ID NO: 428)) that were 61 bp and 62 bp respectively, from the TTAA (SEQ ID NO: 1) targeted site.

[0282] KOD One polymerase was used: 10 ul reaction, and 1 ul of direct lysis as template. The primary PCR product was diluted 1:50 in water. Then, 1 ul of the 1:50 dilution was used as a template for Nested PCR, using primers that are nested within the Primary products. PrimeStar GXL polymerase was used (20 ul reaction). The nested PCR products were run on a 1% agarose gel (FIG. 24C), a band of the expected size was sequenced. The sequences were aligned and positive insertions were identified--those that include genomic sequence with the TTAA (SEQ ID NO: 1) insertions site and the edge of the transposon insert (FIG. 24D).

Targeted Genomic Integration Site Recovery

[0283] Pellets from stable transfections of HEK293 cells were lysed using the DirectPCR Cell lysis buffer (Viagen Biotech) for use as template for nested PCR to identify targeted transposon insertions. In order to optimize the PCR, the lysate template was used at three dilutions, 1:1, 1:4 and 1:8. Forward primers were designed to extend outward from the transposon whereas reverse primers were designed to extend from the ROSA26 target sequence (FIG. 24B). A 10 uL primary PCR was performed using the KOD Xtreme Hot Start DNA Polymerase (Novagen) that was diluted 1:50 in H.sub.2O and used as template for a 20 uL nested PCR using PrimeSTAR GXL DNA Polymerase (Clontech). Amplification products were gel purified with the Zymoclean Gel DNA Recovery Kit (Zymo Research) and sequenced directly or cloned into pJet1.2 (Thermo Fisher) for sequencing. Sequences were aligned against the transposon sequence using BLAST and against the human reference genome (hg38) using BLAT to identify insertion site locations.

RNA-Guided Transposition to the Genome

[0284] We tested the ability of our dCas9-piggyBac fusion constructs to deliver a transgene to the human ROSA26 safe harbor locus. The donor plasmid was cotransfected with dCas9-PB, dCas9-H2 or dCas9 H3 each with 0, 4 or 8 guides, in duplicate. Following 3 weeks of antibiotic selection, the cultures were lysed for use as template for genomic PCR. To improve the chances of recovering insertions, three dilutions of the lysate template were used. Primary PCR primers were designed to extend out from each side of the transposon. Four additional primary PCR primers were designed to extend towards the target site in ROSA26 (two on each side). Individual PCR reactions were performed using all pair-wise primer combinations (eight total). Products arising from the primary PCR reactions were used as template for nested PCR. Sequenced products included the flanking TRE of the transposon, the canonical TTAA (SEQ ID NO: 1) sequence at the junction and the genomic sequence flanking the insertion site.

Results

[0285] In the present study, a total of 22 insert junctions were recovered, which are shown in FIG. 24A. The present study demonstrated RNA-guided transposition to ROSA26 in human cells and provided a proof-of-concept for directing integration deficient (Int-) PB transposase mutants to human ROSA26, for gene therapy use.

[0286] The present study also demonstrates that the inventors were able to target one specific TTAA (SEQ ID NO: 1) site at ROSA26 using MLT fused to dCas9 by intein splicing and gRNA.

[0287] It was observed that helper MLT-TALE and MLT-Cas9/gRNA transposases expression targets hROSA26 at a specific TTAA (SEQ ID NO: 1) site (FIG. 24B, FIG. 24C, and FIG. 24D) used genomic PCR to recover targeted insertions to human ROSA26. Despite millions of potential TTAA (SEQ ID NO: 1) sequences available for insertion throughout the genome, a number of inserted transposons adjacent to the gRNA target sequence were uncovered. Control transfections without gRNA did not result in any targeted insertions. The results shown in FIG. 24B, FIG. 24C, and FIG. 24D demonstrate that a transgene was successfully integrated into the genomic safe harbor site, hROSA26, without a footprint (as shown by DNA sequencing). This indicates that any gene can be placed in that TTAA (SEQ ID NO: 1) location.

Example 9--Study of Integration in Various Cell Lines (FACs) Using MLT Transposase (RNA Helper)

[0288] An objective of this study was to use the MLT transposase of the present disclosure and CMV-GFP to integrate into four different cell lines (HEK293, Huh7, CHO-K1, and T-cells), to compare the efficiency of integration for various cell lines. A further objective was to integrate CMV-GFP only, to determine whether the MLT transposase had an effect on cell viability. This was quantified by using FACs to measure GFP expression in each cell line, once it was integrated.

[0289] The following protocol was used: [0290] CHO-K1, HEK293, HUH7, and-T-cells were seeded at three different cell densities. [0291] Nucleofection efficiency of the three cell lines was tested using the Cell Line 4D-Nucleofector.TM. Kit and program (Lonza Bioscience) using 0.4 .mu.g of pmaxGFP.TM. Vector (following the provider's recommendation for each specific cell line) as a positive control. [0292] Measurement of GFP expression was assessed using high-content analysis (visual) and flowcytometry (quantitative) at two timepoints (24 h and 72 h). Nuclei were stained and quantified with Hoechst33342 vital dye. Percentage of GFP positive cells was calculated. As T-cells are suspension cells, only flow cytometry read-out was performed.

Results

[0293] All of the studied cell lines (CHO-K1, HEK293, HUH7, and-T-cells) were more than 80% nucleofected. All of the cell lines showed 85-95% GFP expression in presence or absence of the MLT transposase after three days of nucleofection, as shown in FIGS. 25 to 28.

[0294] FIG. 25 shows initial Huh7 cell lines transfected under different conditions to show that Huh7 express GFP. The rows show (from the top) untreated cells, mock transfections (without a nucleic acid), cells treated with MLT, and cells treated with pmaxGFP; the columns show controls at day 1 (D1), day 3 (D3), and day 7 (D7).

[0295] FIG. 26 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only, at different ratios, 24 hours post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0296] FIG. 27 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only at different ratios, 72 hours post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0297] FIG. 28 shows Huh7 cells transfected with CMV-GFP+ MLT, compared to cells transfected with CMV-GFP only at different ratios, 1 week post transfection. The top row shows cells transfected with a CMV-GFP:MLT ratio of 2:1 .mu.g, and cells transfected with CMV-GFP only (2 .mu.g). The middle row shows cells transfected with a CMV-GFP:MLT ratio of 1:1 .mu.g, and the cells transfected with CMV-GFP only (1 .mu.g). The bottom row shows cells transfected with a CMV-GFP:MLT ratio of 0.5:1 .mu.g, and the cells transfected with CMV-GFP only (0.5 .mu.g).

[0298] FIG. 29A shows the viability of HEK293 cells at 14 and 21 days after transfection using CMV-GFP MLT DNA donor and a MLT RNA helper. There was no apparent toxicity due to lipofectamine, DNA or RNA. Robust GFP expression was found in over 40% of the cells after 14 and 21 days (FIG. 29B). Integration efficiency was analyzed FACs and showed that 37% of cells were stably integrated with the MLT donor DNA (FIG. 29C and FIG. 29D).

[0299] FIG. 29E shows the percentage of GFP positive HEK293 cells after nucleofection lipofection in T25 flasks. The % GFP positive cells was the same in CMV-GFP MLT Donor alone compared to CMV-GFP MLT Donor plus MLT Helper RNA. The % GFP positivity declined rapidly in HEK293 cells transfected with CMV-GFP MLT Donor alone and reached 5% at Day 21. The % GFP positivity stabilized in HEK293 cells transfected with CMV-GFP MLT Donor plus MLT Helper RNA and reached 42% at Day 21. The integration efficiency was calculated at 37%. Gated FACs was able to select GFP positive and mnCHerry positive cell populations in order to evaluate the effects of RNA expression (mCherry) (FIG. 30A-D).

Example 10--Transposition of HT1080 Cells Using CMV-GFP/MLT Transposase

[0300] An objective of this study was to transfect HT1080 cells with CMV-GFP MLT DNA Donor and MLT DNA Helper transposase 1 or MLT DNA Helper transposase 2, and quantify their transposition efficiency by comparing their GFP expression. HT1080 is a human fibrosarcoma cell line.

[0301] FIG. 31 shows CMV-GFP MLT DNA Donor expression 24 hours post transfection of HT1080 cells, and FIG. 32 shows CMV-GFP MLT DNA Donor expression 2 weeks post transfection of HT1080 cells.

[0302] As shown in FIG. 31, both MLT DNA Helper transposase 1 and MLT DNA Helper transposase 2 effectively transfected the HT1080 cells when combined with CMV-GFP MLT Donor DNA. Both of these transposases expressed very similar levels of GFP, while the donor DNA-only (CMV-GFP only) demonstrated that GFP can be expressed in these cells. The untransfected cell line had no GFP expression, since none is present in this cell line.

[0303] After 2 weeks, as shown in FIG. 32, less GFP expression was observed from MLT DNA Helper transposase 1 and MLT DNA Helper transposase 2, while the MLT DNA Helper transposase 2 expressed GFP slightly stronger when compared to the MLT DNA Helper transposase 1. The CMV-GFP only (donor DNA only) and the untransfected cells had no GFP expression, because the donor DNA did not integrate into the cell line while the untransfected cell never expressed GFP to begin with.

[0304] In this study, when comparing the transfection efficiency of the MLT DNA Helper transposase 1 and MLT DNA Helper transposase 2 in HT1080 cells, the MLT DNA Helper transposase 2 with CMV-GFP MLT DNA Donor was shown to more effectively transfect the HT1080 cells (FIG. 32, 2 weeks post-transfection). Although the integration efficiency is comparable between The MLT RNA Helper transposase 2 and MLT DNA Helper transposase 2, the MLT DNA Helper transposase 2 is more suitable for transfection of cell lines, including for ex-vivo experiments.

Definitions

[0305] The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs.

[0306] The term "in vivo" refers to an event that takes place in a subject's body.

[0307] The term "ex vivo" refers to an event which involves treating or performing a procedure on a cell, tissue and/or organ which has been removed from a subject's body. Aptly, the cell, tissue and/or organ may be returned to the subject's body in a method of treatment or surgery.

[0308] As used herein, the term "variant" encompasses but is not limited to nucleic acids or proteins which comprise a nucleic acid or amino acid sequence which differs from the nucleic acid or amino acid sequence of a reference by way of one or more substitutions, deletions and/or additions at certain positions. The variant may comprise one or more conservative substitutions. Conservative substitutions may involve, e.g., the substitution of similarly charged or uncharged amino acids.

[0309] "Carrier" or "vehicle" as used herein refer to carrier materials suitable for drug administration. Carriers and vehicles useful herein include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, surfactant, lipid or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.

[0310] The phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

[0311] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.

[0312] As used herein, "a," "an," or "the" can mean one or more than one.

[0313] Further, the term "about" when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language "about 50" covers the range of 45 to 55.

[0314] As used herein, the word "include," and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0315] Although the open-ended term "comprising," as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as "consisting of" or "consisting essentially of."

[0316] As used herein, the words "preferred" and "preferably" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

EQUIVALENTS

[0317] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein set forth and as follows in the scope of the appended claims.

[0318] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

[0319] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0320] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0321] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 428 <210> SEQ ID NO 1 <211> LENGTH: 4 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 1 ttaa 4 <210> SEQ ID NO 2 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 2 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 3 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 3 atggcccagc acagcgacta cagcgacgac gagttctgtg ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 4 <211> LENGTH: 568 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 4 Met Ser Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Trp Ser Pro Tyr Thr Asp Ser Trp Tyr His 290 295 300 Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala Leu 305 310 315 320 Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg Gly 325 330 335 Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr Lys 340 345 350 Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys Lys 355 360 365 Pro Val Tyr Leu Ile Ser Ser His Ser Ala Glu Met Glu Glu Ser Gln 370 375 380 Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn Ala Leu 385 390 395 400 Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp Gln Tyr 405 410 415 Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Trp Lys Trp Thr Lys Arg Leu 420 425 430 Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr Ala Val Tyr 435 440 445 Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe Leu Lys Gln 450 455 460 Thr Ala His Trp Leu Thr Asp Asp Ile Pro Glu Asp Met Asp Ile Val 465 470 475 480 Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met Arg Ala Lys Pro 485 490 495 Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp Met Arg Lys His 500 505 510 Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys Asn Ile Leu Arg 515 520 525 Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser Glu Thr Arg Tyr 530 535 540 Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly Ala Cys Phe Glu 545 550 555 560 Lys Tyr His Thr Leu Lys Asn Tyr 565 <210> SEQ ID NO 5 <211> LENGTH: 1716 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 5 atgtcgcagc attcagacta ttctcatgat gagttttgtg cagacaagtt gtccaattat 60 tcttgtgata gcgatcttga aaatgcgagt acaagtgatg aagattctag tgatgatgaa 120 gtaatggtgc gtcccaggac attgaggcga cgaagaattt cgagctccag ctctgactca 180 gagtcagata tagaaggcgg gagagaagaa tggtcgcatg ttgataatcc accggtctta 240 gaagattttt tagggcatca aggattaaac acagatgctg ttataaataa tatagaagat 300 gccgtgaaat tatttatcgg agatgatttt tttgaatttc ttgtagagga gtcaaacagg 360 tattataatc aaaataggaa taatttcaaa ctttcaaaaa aaagcctaaa gtggaaagat 420 ataacccctc aagagatgaa gaagttttta gggttaattg ttctcatggg acaggtgcgc 480 aaagatagaa gagatgacta ttggaccacg gagccatgga cggagacgcc atattttggt 540 aaaacgatga cgagagacag gttccgacag atatggaaag cttggcactt caataataat 600 gcggatatcg taaatgaatc agatagactt tgcaaagtga gaccagtact agattatttt 660 gtgcctaaat ttataaatat ttacaaacct catcagcaat tatcactaga tgaagggatc 720 gtaccttgga ggggaagatt attctttagg gtatataatg ctggcaagat cgttaaatat 780 ggaatattgg ttcgtttgtt gtgcgaaagt gatacaggat atatctgtaa catggaaatt 840 tattgcggcg aaggaaagcg attattggaa acgatacaaa cagtagtgtc tccatacact 900 gattcgtggt accatatata tatggacaat tattataata gcgtcgcaaa ttgtgaagca 960 cttatgaaaa acaaattcag aatatgtgga acaatccgga aaaatcgagg tatacctaaa 1020 gattttcaaa caatttcttt gaaaaaaggt gaaacaaaat ttataaggaa aaatgatata 1080 ttgttacaag tgtggcaatc aaaaaagcct gtatacctga tttcttcgat tcattctgcg 1140 gagatggaag aaagtcagaa tattgacaga acatcaaaaa agaaaattgt caaaccgaat 1200 gcactcattg actacaataa acatatgaaa ggtgttgacc gggccgacca atacctttca 1260 tattattcga tattgcggag gacggtcaaa tggacaaaaa ggttggcaat gtatatgata 1320 aattgcgcat tatttaattc ttatgcagtt tacaaatcag tgaggcaaag aaaaatgggt 1380 tttaaaatgt ttttgaaaca aacagctatc cactggttga cggatgatat tccagaggac 1440 atggacattg ttccagacct tcaaccagta ccgtctactt ctggaatgcg ggctaaacca 1500 cctacatctg atccaccatg caggctatcg atggacatga gaaagcatac gttacaggca 1560 attgtcggaa gtggaaaaaa gaaaaacatt ttgagaaggt gtcgcgtatg ttccgttcat 1620 aaattgcgca gtgagacacg ctacatgtgc aaattttgca atatacctct acataaaggg 1680 gcgtgttttg aaaaatatca tacgctaaaa aactat 1716 <210> SEQ ID NO 6 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 6 atggcccagc acagcgacta cagcgacgac gagttctgtg ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaagagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 7 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 7 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Lys Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 8 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 8 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 9 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 9 Met Ala Gln His Ser Asp Tyr Pro Asp Asp Glu Phe Arg Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 10 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 10 Met Gly Ser Ser Leu Asp Asp Glu His Ile Leu Ser Ala Leu Leu Gln 1 5 10 15 Ser Asp Asp Glu Leu Val Gly Glu Asp Ser Asp Ser Glu Ile Ser Asp 20 25 30 His Val Ser Glu Asp Asp Val Gln Ser Asp Thr Glu Glu Ala Phe Ile 35 40 45 Asp Glu Val His Glu Val Gln Pro Thr Ser Ser Gly Ser Glu Ile Leu 50 55 60 Asp Glu Gln Asn Val Ile Glu Gln Pro Gly Ser Ser Leu Ala Ser Asn 65 70 75 80 Lys Ile Leu Thr Leu Pro Gln Arg Thr Ile Arg Gly Lys Asn Lys His 85 90 95 Cys Trp Ser Thr Ser Lys Ser Thr Arg Arg Ser Arg Val Ser Ala Leu 100 105 110 Asn Ile Val Arg Ser Gln Arg Gly Pro Thr Arg Met Cys Arg Asn Ile 115 120 125 Tyr Asp Pro Leu Leu Cys Phe Lys Leu Phe Phe Thr Asp Glu Ile Ile 130 135 140 Ser Glu Ile Val Lys Trp Thr Asn Ala Glu Ile Ser Leu Lys Arg Arg 145 150 155 160 Glu Ser Met Thr Gly Ala Thr Phe Arg Asp Thr Asn Glu Asp Glu Ile 165 170 175 Tyr Ala Phe Phe Gly Ile Leu Val Met Thr Ala Val Arg Lys Asp Asn 180 185 190 His Met Ser Thr Asp Asp Leu Phe Asp Arg Ser Leu Ser Met Val Tyr 195 200 205 Val Ser Val Met Ser Arg Asp Arg Phe Asp Phe Leu Ile Arg Cys Leu 210 215 220 Arg Met Asp Asp Lys Ser Ile Arg Pro Thr Leu Arg Glu Asn Asp Val 225 230 235 240 Phe Thr Pro Val Arg Lys Ile Trp Asp Leu Phe Ile His Gln Cys Ile 245 250 255 Gln Asn Tyr Thr Pro Gly Ala His Leu Thr Ile Asp Glu Gln Leu Leu 260 265 270 Gly Phe Arg Gly Arg Cys Pro Phe Arg Met Tyr Ile Pro Asn Lys Pro 275 280 285 Ser Lys Tyr Gly Ile Lys Ile Leu Met Met Cys Asp Ser Gly Thr Lys 290 295 300 Tyr Met Ile Asn Gly Met Pro Tyr Leu Gly Arg Gly Thr Gln Thr Asn 305 310 315 320 Gly Val Pro Leu Gly Glu Tyr Tyr Val Lys Glu Leu Ser Lys Pro Val 325 330 335 Arg Gly Ser Cys Arg Asn Ile Thr Cys Asp Asn Trp Phe Thr Ser Ile 340 345 350 Pro Leu Ala Lys Asn Leu Leu Gln Glu Pro Tyr Lys Leu Thr Ile Val 355 360 365 Gly Thr Val Arg Ser Asn Lys Arg Glu Ile Pro Glu Val Leu Lys Asn 370 375 380 Ser Arg Ser Arg Pro Val Gly Thr Ser Met Phe Cys Phe Asp Gly Pro 385 390 395 400 Leu Thr Leu Val Ser Tyr Lys Pro Lys Pro Ala Lys Met Val Tyr Leu 405 410 415 Leu Ser Ser Cys Asp Glu Asp Ala Ser Ile Asn Glu Ser Thr Gly Lys 420 425 430 Pro Gln Met Val Met Tyr Tyr Asn Gln Thr Lys Gly Gly Val Asp Thr 435 440 445 Leu Asp Gln Met Cys Ser Val Met Thr Cys Ser Arg Lys Thr Asn Arg 450 455 460 Trp Pro Met Ala Leu Leu Tyr Gly Met Ile Asn Ile Ala Cys Ile Asn 465 470 475 480 Ser Phe Ile Ile Tyr Ser His Asn Val Ser Ser Lys Gly Glu Lys Val 485 490 495 Gln Ser Arg Lys Lys Phe Met Arg Asn Leu Tyr Met Ser Leu Thr Ser 500 505 510 Ser Phe Met Arg Lys Arg Leu Glu Ala Pro Thr Leu Lys Arg Tyr Leu 515 520 525 Arg Asp Asn Ile Ser Asn Ile Leu Pro Asn Glu Val Pro Gly Thr Ser 530 535 540 Asp Asp Ser Thr Glu Glu Pro Val Thr Lys Lys Arg Thr Tyr Cys Thr 545 550 555 560 Tyr Cys Pro Ser Lys Ile Arg Arg Lys Ala Asn Ala Ser Cys Lys Lys 565 570 575 Cys Lys Lys Val Ile Cys Arg Glu His Asn Ile Asp Met Cys Gln Ser 580 585 590 Cys Phe <210> SEQ ID NO 11 <211> LENGTH: 280 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 11 Met Ser Asn Pro Arg Lys Arg Ser Ile Pro Thr Cys Asp Val Asn Phe 1 5 10 15 Val Leu Glu Gln Leu Leu Ala Glu Asp Ser Phe Asp Glu Ser Asp Phe 20 25 30 Ser Glu Ile Asp Asp Ser Asp Asp Phe Ser Asp Ser Ala Ser Glu Asp 35 40 45 Tyr Thr Val Arg Pro Pro Ser Asp Ser Glu Ser Asp Gly Asn Ser Pro 50 55 60 Thr Ser Ala Asp Ser Gly Arg Ala Leu Lys Trp Ser Thr Arg Val Met 65 70 75 80 Ile Pro Arg Gln Arg Tyr Asp Phe Thr Gly Thr Pro Gly Arg Lys Val 85 90 95 Asp Val Ser Asp Thr Thr Asp Pro Leu Gln Tyr Phe Glu Leu Phe Phe 100 105 110 Thr Glu Glu Leu Val Ser Lys Ile Thr Ser Glu Met Asn Ala Gln Ala 115 120 125 Ala Leu Leu Ala Ser Lys Pro Pro Gly Pro Lys Gly Phe Ser Arg Met 130 135 140 Asp Lys Trp Lys Asp Thr Asp Asn Asp Glu Leu Lys Val Phe Phe Ala 145 150 155 160 Val Met Leu Leu Gln Gly Ile Val Gln Lys Pro Glu Leu Glu Met Phe 165 170 175 Trp Ser Thr Arg Pro Leu Leu Asp Ile Pro Tyr Leu Arg Gln Ile Met 180 185 190 Thr Gly Glu Arg Phe Leu Leu Leu Leu Arg Cys Leu His Phe Val Asn 195 200 205 Asn Ser Ser Ile Ser Ala Gly Gln Ser Lys Ala Gln Ile Ser Leu Gln 210 215 220 Lys Ile Lys Pro Val Phe Asp Phe Leu Val Asn Lys Phe Ser Thr Val 225 230 235 240 Tyr Thr Pro Asn Arg Asn Ile Ala Val Asp Glu Ser Leu Met Leu Phe 245 250 255 Lys Gly Arg Leu Ala Met Lys Gln Tyr Ile Pro Thr Lys Met Asn Leu 260 265 270 Lys Asp Ser Ala Asp Gly Leu Lys 275 280 <210> SEQ ID NO 12 <211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 12 Met Asp Leu Arg Cys Gln His Thr Val Leu Ser Ile Arg Glu Ser Arg 1 5 10 15 Gly Leu Leu Pro Asn Leu Lys Met Lys Thr Ser Arg Met Lys Lys Gly 20 25 30 Asp Ile Ile Phe Ser Arg Lys Gly Asp Ile Leu Leu Leu Ala Trp Lys 35 40 45 Asp Lys Arg Val Val Arg Met Ile Ser Ile His Asp Thr Ser Val Ser 50 55 60 Thr Thr Gly Lys Lys Asn Arg Lys Thr Gly Glu Asn Ile Val Lys Pro 65 70 75 80 Ala Cys Ile Lys Glu Tyr Asn Ala His Met Lys Gly Val Asp Arg Ala 85 90 95 Asp Gln Phe Leu Ser Cys Cys Ser Ile Leu Arg Lys Met Met Lys Trp 100 105 110 Thr Lys Lys Val Val Leu Tyr Leu Ile Asn Cys Gly Leu Phe Asn Ser 115 120 125 Phe Arg Val Tyr Asn Val Leu Asn Pro Gln Ala Lys Met Lys Tyr Lys 130 135 140 Gln Phe Leu Leu Ser Val Ala Arg Asp Trp Ile Met Asp Asp Asn Asn 145 150 155 160 Glu Gly Ser Pro Glu Pro Glu Thr Asn Leu Ser Ser Pro Ser Pro Gly 165 170 175 Gly Ala Arg Arg Ala Pro Arg Lys Asp Pro Pro Lys Arg Leu Ser Gly 180 185 190 Asp Met Lys Gln His Glu Pro Thr Cys Ile Pro Ala Ser Gly Lys Lys 195 200 205 Lys Phe Pro Thr Arg Ala Cys Arg Val Cys Ala His Gly Lys Arg Ser 210 215 220 Glu Ser Arg Tyr Leu Cys Lys Phe Cys Leu Val Pro Leu His Arg Gly 225 230 235 240 Lys Cys Phe Thr Gln Tyr His Thr Leu Lys Lys Tyr 245 250 <210> SEQ ID NO 13 <211> LENGTH: 432 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 13 Met Lys Ala Phe Leu Gly Val Ile Leu Asn Met Gly Val Leu Asn His 1 5 10 15 Pro Asn Leu Gln Ser Tyr Trp Ser Met Asp Phe Glu Ser His Ile Pro 20 25 30 Phe Phe Arg Ser Val Phe Lys Arg Glu Arg Phe Leu Gln Ile Phe Trp 35 40 45 Met Leu His Leu Lys Asn Asp Gln Lys Ser Ser Lys Asp Leu Arg Thr 50 55 60 Arg Thr Glu Lys Val Asn Cys Phe Leu Ser Tyr Leu Glu Met Lys Phe 65 70 75 80 Arg Glu Arg Phe Cys Pro Gly Arg Glu Ile Ala Val Asp Glu Ala Val 85 90 95 Val Gly Phe Lys Gly Lys Ile His Phe Ile Thr Tyr Asn Pro Lys Lys 100 105 110 Pro Thr Lys Trp Gly Ile Arg Leu Tyr Val Leu Ser Asp Ser Lys Cys 115 120 125 Gly Tyr Val His Ser Phe Val Pro Tyr Tyr Gly Gly Ile Thr Ser Glu 130 135 140 Thr Leu Val Arg Pro Asp Leu Pro Phe Thr Ser Arg Ile Val Leu Glu 145 150 155 160 Leu His Glu Arg Leu Lys Asn Ser Val Pro Gly Ser Gln Gly Tyr His 165 170 175 Phe Phe Thr Asp Arg Tyr Tyr Thr Ser Val Thr Leu Ala Lys Glu Leu 180 185 190 Phe Lys Glu Lys Thr His Leu Thr Gly Thr Ile Met Pro Asn Arg Lys 195 200 205 Asp Asn Pro Pro Val Ile Lys His Gln Lys Leu Lys Lys Gly Glu Ile 210 215 220 Val Ala Phe Arg Asp Glu Asn Val Met Leu Leu Ala Trp Lys Asp Lys 225 230 235 240 Arg Ile Val Thr Leu Ser Thr Trp Asp Ser Glu Thr Glu Ser Val Glu 245 250 255 Arg Arg Val Gly Gly Gly Lys Glu Ile Val Leu Lys Pro Lys Val Val 260 265 270 Thr Asn Tyr Thr Lys Phe Met Gly Gly Val Asp Ile Ala Asp Tyr Thr 275 280 285 Ser Thr Tyr Cys Phe Met Arg Lys Thr Leu Lys Trp Trp Arg Thr Leu 290 295 300 Phe Phe Trp Gly Leu Glu Val Ser Val Val Asn Ser Tyr Ile Leu Tyr 305 310 315 320 Lys Glu Cys Gln Lys Arg Lys Asn Glu Lys Pro Ile Thr His Val Lys 325 330 335 Phe Ile Arg Lys Leu Val His Asp Leu Val Gly Glu Phe Arg Asp Gly 340 345 350 Thr Leu Thr Ser Arg Gly Arg Leu Leu Ser Thr Asn Leu Glu Gln Arg 355 360 365 Leu Asp Gly Lys Leu His Ile Ile Thr Pro His Pro Asn Lys Lys His 370 375 380 Lys Asp Cys Val Val Cys Ser Asn Arg Lys Ile Lys Gly Gly Arg Arg 385 390 395 400 Glu Thr Ile Tyr Ile Cys Glu Thr Cys Glu Cys Lys Pro Gly Leu His 405 410 415 Val Gly Glu Cys Phe Lys Lys Tyr His Thr Met Lys Asn Tyr Arg Asp 420 425 430 <210> SEQ ID NO 14 <211> LENGTH: 662 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 14 Met Pro Ser Leu Arg Lys Arg Lys Glu Thr Asn Glu Thr Asp Thr Leu 1 5 10 15 Pro Glu Val Phe Asn Asp Asn Leu Ser Asp Ile Pro Ser Glu Ile Glu 20 25 30 Asp Ala Asp Asp Cys Phe Asp Asp Ser Gly Asp Asp Ser Thr Asp Ser 35 40 45 Thr Asp Ser Glu Ile Ile Arg Pro Val Arg Lys Arg Lys Val Ala Val 50 55 60 Leu Ser Ser Asp Ser Asp Thr Asp Glu Ala Thr Asp Asn Cys Trp Ser 65 70 75 80 Glu Ile Asp Thr Pro Pro Arg Leu Gln Met Phe Glu Gly His Ala Gly 85 90 95 Val Thr Thr Phe Pro Ser Gln Cys Asp Ser Val Pro Ser Val Thr Asn 100 105 110 Leu Phe Phe Gly Asp Glu Leu Phe Glu Met Leu Cys Lys Glu Leu Ser 115 120 125 Asn Tyr His Asp Gln Thr Ala Met Lys Arg Lys Thr Pro Ser Arg Thr 130 135 140 Leu Lys Trp Ser Pro Val Thr Gln Lys Asp Ile Lys Lys Phe Leu Gly 145 150 155 160 Leu Ile Ile Leu Met Gly Gln Thr Arg Lys Asp Ser Leu Lys Asp Tyr 165 170 175 Trp Ser Thr Asp Pro Leu Ile Cys Thr Pro Ile Phe Pro Gln Thr Met 180 185 190 Ser Arg His Arg Phe Glu Gln Ile Trp Thr Phe Trp His Phe Asn Asp 195 200 205 Asn Ala Lys Met Asp Ser Arg Ser Gly Arg Leu Phe Lys Ile Gln Pro 210 215 220 Val Leu Asp Tyr Phe Leu His Lys Phe Arg Thr Ile Tyr Lys Pro Lys 225 230 235 240 Gln Gln Leu Ser Leu Asp Glu Gly Met Ile Pro Trp Arg Gly Arg Phe 245 250 255 Lys Phe Arg Thr Tyr Asn Pro Ala Lys Ile Thr Lys Tyr Gly Leu Leu 260 265 270 Val Arg Met Val Cys Glu Ser Asp Thr Gly Tyr Ile Cys Ser Met Glu 275 280 285 Ile Tyr Thr Ala Glu Gly Arg Lys Leu Gln Glu Thr Val Leu Ser Val 290 295 300 Leu Gly Pro Tyr Leu Gly Ile Trp His His Ile Tyr Gln Asp Asn Tyr 305 310 315 320 Tyr Asn Ala Thr Ser Thr Ala Glu Leu Leu Leu Gln Asn Lys Thr Arg 325 330 335 Val Cys Gly Thr Ile Arg Glu Ser Arg Gly Leu Pro Pro Asn Leu Glu 340 345 350 Met Lys Thr Ser Arg Met Lys Lys Gly Asp Ile Ile Phe Ser Arg Lys 355 360 365 Gly Asp Ile Leu Leu Leu Ala Trp Lys Asp Lys Arg Val Val Arg Met 370 375 380 Ile Ser Thr Ile His Asp Thr Ser Val Ser Thr Thr Gly Lys Lys Asn 385 390 395 400 Arg Lys Thr Gly Glu Asn Ile Val Lys Pro Thr Cys Ile Lys Glu Tyr 405 410 415 Asn Ala His Met Lys Gly Val Asp Arg Ala Asp Gln Phe Leu Ser Cys 420 425 430 Cys Ser Ile Leu Arg Lys Thr Met Lys Trp Thr Lys Lys Val Val Leu 435 440 445 Tyr Leu Ile Asn Cys Gly Leu Phe Asn Ser Phe Arg Val Tyr Asn Val 450 455 460 Leu Asn Pro Gln Ala Lys Met Lys Tyr Lys Gln Phe Leu Leu Ser Val 465 470 475 480 Ala Arg Asp Trp Ile Thr Asp Asp Asn Asn Glu Gly Ser Pro Glu Pro 485 490 495 Glu Thr Asn Leu Ser Ser Pro Ser Pro Gly Gly Ala Arg Arg Ala Pro 500 505 510 Arg Lys Asp Pro Pro Lys Arg Leu Ser Gly Asp Met Lys Gln His Glu 515 520 525 Pro Thr Cys Ile Pro Ala Ser Gly Lys Lys Lys Phe Pro Thr Arg Ala 530 535 540 Cys Arg Val Cys Ala Ala His Gly Lys Arg Ser Glu Ser Arg Tyr Leu 545 550 555 560 Cys Lys Phe Cys Leu Val Pro Leu His Arg Gly Lys Cys Phe Thr Gln 565 570 575 Tyr His Thr Leu Lys Lys Tyr Met Asp Leu Arg Cys Gln His Thr Val 580 585 590 Leu Ser Thr Val Gly Arg Gly Tyr Ser Val Leu Ala Arg Phe Lys Pro 595 600 605 Arg Thr Asn Glu Arg Thr Gly Ser Ser His Cys His Val Gln Val Pro 610 615 620 Ala Gly Gly Gln Gly Pro Pro Ser Thr Ile Ile Ala Asn Gly Cys Gly 625 630 635 640 Cys Lys Leu Glu Pro Met Val Arg Thr Arg Ser Pro Thr Cys Leu Val 645 650 655 Ile Glu Phe Gly Cys Met 660 <210> SEQ ID NO 15 <211> LENGTH: 673 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 15 Met Pro Ser Leu Arg Lys Arg Lys Glu Thr Asn Glu Thr Asp Thr Leu 1 5 10 15 Pro Glu Val Phe Asn Asp Asn Leu Ser Asp Ile Pro Ser Glu Ile Glu 20 25 30 Asp Ala Asp Asp Cys Phe Asp Asp Ser Gly Asp Asp Ser Thr Asp Ser 35 40 45 Thr Glu Ser Glu Ile Ile Arg Pro Val Arg Lys Arg Lys Val Ala Val 50 55 60 Leu Ser Ser Asp Ser Asn Thr Asp Glu Ala Thr Asp Asn Cys Trp Ser 65 70 75 80 Glu Ile Asp Thr Pro Pro Arg Leu Gln Met Phe Glu Gly His Ala Gly 85 90 95 Val Thr Thr Phe Pro Ser Gln Cys Asp Ser Val Pro Ser Val Thr Asn 100 105 110 Leu Phe Phe Gly Asp Glu Leu Phe Glu Met Leu Cys Lys Glu Leu Ser 115 120 125 Asn Tyr His Asp Gln Thr Ala Met Lys Arg Lys Thr Pro Ser Arg Thr 130 135 140 Leu Lys Trp Ser Pro Val Thr Gln Lys Asp Ile Lys Lys Phe Leu Gly 145 150 155 160 Leu Ile Ile Leu Met Gly Gln Thr Arg Lys Asp Ser Trp Lys Asp Tyr 165 170 175 Trp Ser Thr Asp Pro Leu Ile Cys Thr Pro Ile Phe Pro Gln Thr Met 180 185 190 Ser Arg His Arg Phe Glu Gln Ile Trp Thr Phe Trp His Phe Asn Asp 195 200 205 Asn Ala Lys Met Asp Ser Cys Ser Gly Arg Leu Phe Lys Ile Gln Pro 210 215 220 Val Leu Asp Tyr Phe Leu His Lys Phe Arg Thr Ile Tyr Lys Pro Lys 225 230 235 240 Gln Gln Leu Ser Leu Asp Glu Gly Met Ile Pro Trp Arg Gly Arg Leu 245 250 255 Lys Phe Thr Tyr Asn Pro Ala Ile Thr Lys Tyr Gly Leu Leu Val Arg 260 265 270 Met Val Cys Glu Ser Asp Thr Gly Tyr Ile Cys Asn Met Glu Ile Tyr 275 280 285 Thr Ala Glu Arg Lys Lys Leu Gln Glu Thr Val Leu Ser Val Leu Gly 290 295 300 Pro Tyr Leu Gly Ile Trp His His Ile Tyr Gln Asp Asn Tyr Tyr Asn 305 310 315 320 Ala Thr Ser Thr Ala Glu Leu Leu Leu Gln Asn Lys Thr Arg Val Cys 325 330 335 Gly Thr Ile Arg Glu Ser Arg Gly Leu Pro Pro Asn Leu Lys Met Lys 340 345 350 Thr Ser Arg Met Lys Lys Gly Asp Ile Ile Phe Ser Arg Lys Gly Asp 355 360 365 Ile Leu Leu Leu Ala Trp Lys Asp Lys Arg Val Val Arg Met Ile Ser 370 375 380 Thr Ile His Asp Thr Ser Val Ser Thr Thr Gly Lys Lys Asn Arg Lys 385 390 395 400 Thr Gly Glu Asn Ile Val Lys Pro Thr Cys Ile Lys Glu Tyr Asn Ala 405 410 415 His Met Lys Gly Val Asp Arg Ala Asp Gln Phe Leu Ser Cys Cys Ser 420 425 430 Ile Leu Arg Lys Thr Thr Lys Trp Thr Lys Lys Val Val Leu Tyr Leu 435 440 445 Ile Asn Cys Gly Leu Phe Asn Ser Phe Arg Val Tyr Asn Ile Leu Asn 450 455 460 Pro Gln Ala Lys Met Lys Tyr Lys Gln Phe Leu Leu Ser Val Ala Arg 465 470 475 480 Asp Trp Ile Thr Asp Asp Asn Asn Glu Gly Ser Pro Glu Pro Glu Thr 485 490 495 Asn Leu Ser Ser Pro Ser Ser Gly Gly Ala Arg Arg Ala Pro Arg Lys 500 505 510 Asp Gln Pro Lys Arg Leu Ser Gly Asp Met Lys Gln His Glu Pro Thr 515 520 525 Cys Ile Pro Ala Ser Gly Lys Lys Lys Phe Pro Thr Ala Cys Arg Val 530 535 540 Cys Ala Ala His Gly Lys Arg Ser Glu Ser Arg Tyr Leu Arg Lys Phe 545 550 555 560 Cys Phe Val Pro Leu Arg Gly Lys Cys Phe Met Tyr His Thr Leu Lys 565 570 575 Lys Tyr Ser Glu Leu Phe Ser Leu Ile Val Val Ser Lys Ile Gln Asn 580 585 590 Val Ile Ile Tyr Lys Thr Thr Lys Val Tyr Met Arg Tyr Val Met Arg 595 600 605 Ser His Cys Pro Leu Ser Phe Leu Val Phe Ala Pro Ser Val Lys Asp 610 615 620 Arg Ser Arg Val Phe Ser Phe Phe Thr Arg His Leu Leu Trp Thr Leu 625 630 635 640 Asp Val Asn Thr Leu Ser Cys Pro His Arg Met Lys Arg Ser His Trp 645 650 655 Trp Lys Pro Cys Arg Ser Ile Tyr Glu Lys Leu Tyr Asn Cys Thr Asn 660 665 670 Pro <210> SEQ ID NO 16 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 16 Met Asp Leu Arg Cys Gln His Thr Val Leu Ser Ile Arg Glu Ser Arg 1 5 10 15 Gly Leu Pro Pro Asn Leu Lys Met Lys Thr Ser Arg Met Lys Lys Gly 20 25 30 Asp Ile Ile Phe Ser Arg Lys Gly Asp Ile Leu Leu Leu Ala Trp Lys 35 40 45 Asp Lys Arg Val Val Arg Met Ile Ser Thr Ile His Asp Thr Ser Val 50 55 60 Ser Thr Thr Gly Lys Lys Asn Arg Lys Thr Gly Glu Asn Ile Val Lys 65 70 75 80 Pro Ala Cys Ile Lys Glu Tyr Asn Ala His Met Lys Gly Val Asp Arg 85 90 95 Ala Asp Gln Phe Leu Ser Cys Cys Ser Ile Leu Arg Lys Thr Met Lys 100 105 110 Trp Thr Lys Lys Val Val Leu Tyr Leu Ile Asn Cys Gly Leu Phe Asn 115 120 125 Ser Phe Arg Val Tyr Asn Val Leu Asn Pro Gln Ala Lys Met Lys Tyr 130 135 140 Lys Gln Phe Leu Leu Ser Val Ala Arg Asp Trp Ile Thr Asp Asp Asn 145 150 155 160 Asn Glu Gly Ser Pro Glu Pro Glu Thr Asn Leu Ser Ser Pro Ser Pro 165 170 175 Gly Gly Ala Arg Arg Ala Pro Arg Lys Asp Pro Pro Lys Arg Leu Ser 180 185 190 Gly Asp Met Lys Gln His Glu Pro Thr Cys Ile Pro Ala Ser Gly Lys 195 200 205 Lys Lys Phe Pro Thr Arg Ala Cys Arg Val Cys Ala Ala His Gly Lys 210 215 220 Arg Ser Glu Ser Arg Tyr Leu Cys Lys Phe Cys Leu Val Pro Leu His 225 230 235 240 Arg Gly Lys Cys Phe Thr Gln Tyr His Thr Leu Lys Lys Tyr 245 250 <210> SEQ ID NO 17 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 17 Met Gly Ser Ser Leu Asp Asp Glu His Ile Leu Ser Ala Leu Leu Gln 1 5 10 15 Ser Asp Asp Glu Leu Val Gly Glu Asp Ser Asp Ser Glu Val Ser Asp 20 25 30 His Val Ser Glu Asp Asp Val Gln Ser Asp Thr Glu Glu Ala Phe Ile 35 40 45 Asp Glu Val His Glu Val Gln Pro Thr Ser Ser Gly Ser Glu Ile Leu 50 55 60 Asp Glu Gln Asn Val Ile Glu Gln Pro Gly Ser Ser Leu Ala Ser Asn 65 70 75 80 Arg Ile Leu Thr Leu Pro Gln Arg Thr Ile Arg Gly Lys Asn Lys His 85 90 95 Cys Trp Ser Thr Ser Lys Pro Thr Arg Arg Ser Arg Val Ser Ala Leu 100 105 110 Asn Ile Val Arg Ser Gln Arg Gly Pro Thr Arg Met Cys Arg Asn Ile 115 120 125 Tyr Asp Pro Leu Leu Cys Phe Lys Leu Phe Phe Thr Asp Glu Ile Ile 130 135 140 Ser Glu Ile Val Lys Trp Thr Asn Ala Glu Ile Ser Leu Lys Arg Arg 145 150 155 160 Glu Ser Met Thr Ser Ala Thr Phe Arg Asp Thr Asn Glu Asp Glu Ile 165 170 175 Tyr Ala Phe Phe Gly Ile Leu Val Met Thr Ala Val Arg Lys Asp Asn 180 185 190 His Met Ser Thr Asp Asp Leu Phe Asp Arg Ser Leu Ser Met Val Tyr 195 200 205 Val Ser Val Met Ser Arg Asp Arg Phe Asp Phe Leu Ile Arg Cys Leu 210 215 220 Arg Met Asp Asp Lys Ser Ile Arg Pro Thr Leu Arg Glu Asn Asp Val 225 230 235 240 Phe Thr Pro Val Arg Lys Ile Trp Asp Leu Phe Ile His Gln Cys Ile 245 250 255 Gln Asn Tyr Thr Pro Gly Ala His Leu Thr Ile Asp Glu Gln Leu Leu 260 265 270 Gly Phe Arg Gly Arg Cys Pro Phe Arg Val Tyr Ile Pro Asn Lys Pro 275 280 285 Ser Lys Tyr Gly Ile Lys Ile Leu Met Met Cys Asp Ser Gly Thr Lys 290 295 300 Tyr Met Ile Asn Gly Met Pro Tyr Leu Gly Arg Gly Thr Gln Thr Asn 305 310 315 320 Gly Val Pro Leu Gly Glu Tyr Tyr Val Lys Glu Leu Ser Lys Pro Val 325 330 335 His Gly Ser Cys Arg Asn Ile Thr Cys Asp Asn Trp Phe Thr Ser Ile 340 345 350 Pro Leu Ala Lys Asn Leu Leu Gln Glu Pro Tyr Lys Leu Thr Ile Val 355 360 365 Gly Thr Val Arg Ser Asn Lys Arg Glu Ile Pro Glu Val Leu Lys Asn 370 375 380 Ser Arg Ser Arg Pro Val Gly Thr Ser Met Phe Cys Phe Asp Gly Pro 385 390 395 400 Leu Thr Leu Val Ser Tyr Lys Pro Lys Pro Ala Lys Met Val Tyr Leu 405 410 415 Leu Ser Ser Cys Asp Glu Asp Ala Ser Ile Asn Glu Ser Thr Gly Lys 420 425 430 Pro Gln Met Val Met Tyr Tyr Asn Gln Thr Lys Gly Gly Val Asp Thr 435 440 445 Leu Asp Gln Met Cys Ser Val Met Thr Cys Ser Arg Lys Thr Asn Arg 450 455 460 Trp Pro Met Ala Leu Leu Tyr Gly Met Ile Asn Ile Ala Cys Ile Asn 465 470 475 480 Ser Phe Ile Ile Tyr Ser His Asn Val Ser Ser Lys Gly Glu Lys Val 485 490 495 Gln Ser Arg Lys Lys Phe Met Arg Asn Leu Tyr Met Gly Leu Thr Ser 500 505 510 Ser Phe Met Arg Lys Arg Leu Glu Ala Pro Thr Leu Lys Arg Tyr Leu 515 520 525 Arg Asp Asn Ile Ser Asn Ile Leu Pro Lys Glu Val Pro Gly Thr Ser 530 535 540 Asp Asp Ser Thr Glu Glu Pro Val Met Lys Lys Arg Thr Tyr Cys Thr 545 550 555 560 Tyr Cys Pro Ser Lys Ile Arg Arg Lys Ala Ser Ala Ser Cys Lys Lys 565 570 575 Cys Lys Lys Val Ile Cys Arg Glu His Asn Ile Asp Met Cys Gln Ser 580 585 590 Cys Phe <210> SEQ ID NO 18 <211> LENGTH: 1782 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 18 atgggcagca gcctggacga cgagcacatc ctgagcgccc tgctgcagag cgacgacgag 60 ctggtcggcg aggacagcga cagcgaggtg agcgaccacg tgagcgagga cgacgtgcag 120 tccgacaccg aggaggcctt catcgacgag gtgcacgagg tgcagcctac cagcagcggc 180 tccgagatcc tggacgagca gaacgtgatc gagcagcccg gcagctccct ggccagcaac 240 aggatcctga ccctgcccca gaggaccatc aggggcaaga acaagcactg ctggtccacc 300 tccaagccca ccaggcggag cagggtgtcc gccctgaaca tcgtgagaag ccagaggggc 360 cccaccagga tgtgcaggaa catctacgac cccctgctgt gcttcaagct gttcttcacc 420 gacgagatca tcagcgagat cgtgaagtgg accaacgccg agatcagcct gaagaggcgg 480 gagagcatga cctccgccac cttcagggac accaacgagg acgagatcta cgccttcttc 540 ggcatcctgg tgatgaccgc cgtgaggaag gacaaccaca tgagcaccga cgacctgttc 600 gacagatccc tgagcatggt gtacgtgagc gtgatgagca gggacagatt cgacttcctg 660 atcagatgcc tgaggatgga cgacaagagc atcaggccca ccctgcggga gaacgacgtg 720 ttcacccccg tgagaaagat ctgggacctg ttcatccacc agtgcatcca gaactacacc 780 cctggcgccc acctgaccat cgacgagcag ctgctgggct tcaggggcag gtgccccttc 840 agggtctata tccccaacaa gcccagcaag tacggcatca agatcctgat gatgtgcgac 900 agcggcacca agtacatgat caacggcatg ccctacctgg gcaggggcac ccagaccaac 960 ggcgtgcccc tgggcgagta ctacgtgaag gagctgtcca agcccgtcca cggcagctgc 1020 agaaacatca cctgcgacaa ctggttcacc agcatccccc tggccaagaa cctgctgcag 1080 gagccctaca agctgaccat cgtgggcacc gtgagaagca acaagagaga gatccccgag 1140 gtcctgaaga acagcaggtc caggcccgtg ggcaccagca tgttctgctt cgacggcccc 1200 ctgaccctgg tgtcctacaa gcccaagccc gccaagatgg tgtacctgct gtccagctgc 1260 gacgaggacg ccagcatcaa cgagagcacc ggcaagcccc agatggtgat gtactacaac 1320 cagaccaagg gcggcgtgga caccctggac cagatgtgca gcgtgatgac ctgcagcaga 1380 aagaccaaca ggtggcccat ggccctgctg tacggcatga tcaacatcgc ctgcatcaac 1440 agcttcatca tctacagcca caacgtgagc agcaagggcg agaaggtgca gagccggaaa 1500 aagttcatgc ggaacctgta catgggcctg acctccagct tcatgaggaa gaggctggag 1560 gcccccaccc tgaagagata cctgagggac aacatcagca acatcctgcc caaagaggtg 1620 cccggcacca gcgacgacag caccgaggag cccgtgatga agaagaggac ctactgcacc 1680 tactgtccca gcaagatcag aagaaaggcc agcgccagct gcaagaagtg taagaaggtc 1740 atctgccggg agcacaacat cgacatgtgc cagagctgtt tc 1782 <210> SEQ ID NO 19 <211> LENGTH: 205 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 19 ttaaccctag aaagataatc atattgtgac gtacgttaaa gataatcatg cgtaaaattg 60 acgcatgtgt tttatcggtc tgtatatcga ggtttattta ttaatttgaa tagatattaa 120 gttttattat atttacactt acatactaat aataaattca acaaacaatt tatttatgtt 180 tatttattta ttaaaaaaaa acaaa 205 <210> SEQ ID NO 20 <211> LENGTH: 310 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 20 atctataaca agaaaatata tatataataa gttatcacgt aagtagaaca tgaaataaca 60 atataattat cgtatgagtt aaatcttaaa agtcacgtaa aagataatca tgcgtcattt 120 tgactcacgc ggtcgttata gttcaaaatc agtgacactt accgcattga caagcacgcc 180 tcacgggagc tccaagcggc gactgagatg tcctaaatgc acagcgacgg attcgcgcta 240 tttagaaaga gagagcaata tttcaagaat gcatgcgtca attttacgca gactatcttt 300 ctagggttaa 310 <210> SEQ ID NO 21 <211> LENGTH: 157 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 21 ttaacacttg gattgcggga aacgagttaa gtcggctcgc gtgaattgcg cgtactccgc 60 gggagccgtc ttaactcggt tcatatagat ttgcggtgga gtgcgggaaa cgtgtaaact 120 cgggccgatt gtaactgcgt attaccaaat atttgtt 157 <210> SEQ ID NO 22 <211> LENGTH: 212 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 22 aattatttat gtactgaata gataaaaaaa tgtctgtgat tgaataaatt ttcatttttt 60 acacaagaaa ccgaaaattt catttcaatc gaacccatac ttcaaaagat ataggcattt 120 taaactaact ctgattttgc gcgggaaacc taaataattg cccgcgccat cttatatttt 180 ggcgggaaat tcacccgaca ccgtagtgtt aa 212 <210> SEQ ID NO 23 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 23 tggccggcct gaccactgg 19 <210> SEQ ID NO 24 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 24 tgaaggcctg gccggcctg 19 <210> SEQ ID NO 25 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 25 tgagcactga aggcctggc 19 <210> SEQ ID NO 26 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 26 tccactgagc actgaaggc 19 <210> SEQ ID NO 27 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 27 tggtttccac tgagcactg 19 <210> SEQ ID NO 28 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 28 tggggaaaat gacccaaca 19 <210> SEQ ID NO 29 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 29 taggacagtg gggaaaatg 19 <210> SEQ ID NO 30 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 30 tccagggaca cggtgctag 19 <210> SEQ ID NO 31 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 31 tcagagccag gagtcctgg 19 <210> SEQ ID NO 32 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 32 tccttcagag ccaggagtc 19 <210> SEQ ID NO 33 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 33 tcctccttca gagccagga 19 <210> SEQ ID NO 34 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 34 tccagcccct cctccttca 19 <210> SEQ ID NO 35 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 35 tccgagcttg acccttgga 19 <210> SEQ ID NO 36 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 36 tggtttccga gcttgaccc 19 <210> SEQ ID NO 37 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 37 tggggtggtt tccgagcttt ggggtggttt ccgagctt 38 <210> SEQ ID NO 38 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 38 tctgctgggg tggtttccg 19 <210> SEQ ID NO 39 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 39 tgcagagtat ctgctggggt gcagagtatc tgctgggg 38 <210> SEQ ID NO 40 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 40 ccaatcccct cagt 14 <210> SEQ ID NO 41 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 41 cagtgctcag tggaa 15 <210> SEQ ID NO 42 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 42 gaaacatccg gcgactca 18 <210> SEQ ID NO 43 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 43 tcgcccctca aatcttaca 19 <210> SEQ ID NO 44 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 44 tcaaatctta cagctgctc 19 <210> SEQ ID NO 45 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 45 tcttacagct gctcactcc 19 <210> SEQ ID NO 46 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 46 tacagctgct cactcccct 19 <210> SEQ ID NO 47 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 47 tgctcactcc cctgcaggg 19 <210> SEQ ID NO 48 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 48 tcccctgcag ggcaacgcc 19 <210> SEQ ID NO 49 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 49 tgcagggcaa cgcccaggg 19 <210> SEQ ID NO 50 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 50 tctcgattat gggcgggat 19 <210> SEQ ID NO 51 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 51 tcgcttctcg attatgggc 19 <210> SEQ ID NO 52 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 52 tgtcgagtcg cttctcgat 19 <210> SEQ ID NO 53 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 53 tccatgtcga gtcgcttct 19 <210> SEQ ID NO 54 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 54 tcgcctccat gtcgagtcg 19 <210> SEQ ID NO 55 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 55 tcgtcatcgc ctccatgtc 19 <210> SEQ ID NO 56 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 56 tgatctcgtc atcgcctcc 19 <210> SEQ ID NO 57 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 57 gcttcagctt ccta 14 <210> SEQ ID NO 58 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 58 ctgtgatcat gcca 14 <210> SEQ ID NO 59 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 59 acagtggtac acacct 16 <210> SEQ ID NO 60 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 60 ccacccccca ctaag 15 <210> SEQ ID NO 61 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 61 cattggccgg gcac 14 <210> SEQ ID NO 62 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 62 gcttgaaccc aggaga 16 <210> SEQ ID NO 63 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 63 acacccgatc cactggg 17 <210> SEQ ID NO 64 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 64 gctgcatcaa cccc 14 <210> SEQ ID NO 65 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 65 gccacaaaca gaaata 16 <210> SEQ ID NO 66 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 66 ggtggctcat gcctg 15 <210> SEQ ID NO 67 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 67 gatttgcaca gctcat 16 <210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 68 aagctctgag gagca 15 <210> SEQ ID NO 69 <211> LENGTH: 13 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 69 ccctagctgt ccc 13 <210> SEQ ID NO 70 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 70 gcctagcatg ctag 14 <210> SEQ ID NO 71 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 71 atgggcttca cggat 15 <210> SEQ ID NO 72 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 72 gaaactatgc ctgc 14 <210> SEQ ID NO 73 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 73 gcaccattgc tccc 14 <210> SEQ ID NO 74 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 74 gacatgcaac tcag 14 <210> SEQ ID NO 75 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 75 acaccactag gggt 14 <210> SEQ ID NO 76 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 76 gtctgctaga cagg 14 <210> SEQ ID NO 77 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 77 ggcctagaca ggctg 15 <210> SEQ ID NO 78 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 78 gaggcattct tatcg 15 <210> SEQ ID NO 79 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 79 gcctggaaac gttcc 15 <210> SEQ ID NO 80 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 80 gtgctctgac aata 14 <210> SEQ ID NO 81 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 81 gttttgcagc ctcc 14 <210> SEQ ID NO 82 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 82 acagctgtgg aacgt 15 <210> SEQ ID NO 83 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 83 ggctctcttc ctcct 15 <210> SEQ ID NO 84 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 84 ctatcccaaa actct 15 <210> SEQ ID NO 85 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 85 gaaaaactat gtat 14 <210> SEQ ID NO 86 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 86 aggcaggctg gttga 15 <210> SEQ ID NO 87 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 87 caatacaacc acgc 14 <210> SEQ ID NO 88 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 88 atgacggact caact 15 <210> SEQ ID NO 89 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 89 cacaacattt gtaa 14 <210> SEQ ID NO 90 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 90 atttccagtg caca 14 <210> SEQ ID NO 91 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 91 gtttagctca cccgtgagcc 20 <210> SEQ ID NO 92 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 92 cccaatatta ttgttctctg 20 <210> SEQ ID NO 93 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 93 ggggtgggat aggggatacg 20 <210> SEQ ID NO 94 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 94 ggatccccct ctacatttaa 20 <210> SEQ ID NO 95 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 95 gtgatcttgt acaaatcatt 20 <210> SEQ ID NO 96 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 96 ctacacagaa tctgttagaa 20 <210> SEQ ID NO 97 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 97 taagctagag aatagatctc 20 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 98 tcaatacact taatgattta 20 <210> SEQ ID NO 99 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 99 caccgggagc cacgaaaaca gatcc 25 <210> SEQ ID NO 100 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 100 caccgcgaaa acagatccag ggaca 25 <210> SEQ ID NO 101 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 101 caccgagatc cagggacacg gtgct 25 <210> SEQ ID NO 102 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 102 caccggacac ggtgctagga cagtg 25 <210> SEQ ID NO 103 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 103 caccggaaaa tgacccaaca gcctc 25 <210> SEQ ID NO 104 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 104 caccggcctg gccggcctga ccact 25 <210> SEQ ID NO 105 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 105 caccgctgag cactgaaggc ctggc 25 <210> SEQ ID NO 106 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 106 caccgtggtt tccactgagc actga 25 <210> SEQ ID NO 107 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 107 caccggatag ccaggagtcc tttcg 25 <210> SEQ ID NO 108 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 108 caccggcgct tccagtgctc agact 25 <210> SEQ ID NO 109 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 109 caccgcagtg ctcagactag ggaag 25 <210> SEQ ID NO 110 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 110 caccggcccc tcctccttca gagcc 25 <210> SEQ ID NO 111 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 111 caccgtcctt cagagccagg agtcc 25 <210> SEQ ID NO 112 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 112 caccgtggtt tccgagcttg accct 25 <210> SEQ ID NO 113 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 113 caccgctgca gagtatctgc tgggg 25 <210> SEQ ID NO 114 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 114 caccgcgttc ctgcagagta tctgc 25 <210> SEQ ID NO 115 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 115 aaacggatct gttttcgtgg ctccc 25 <210> SEQ ID NO 116 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 116 aaactgtccc tggatctgtt ttcgc 25 <210> SEQ ID NO 117 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 117 aaacagcacc gtgtccctgg atctc 25 <210> SEQ ID NO 118 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 118 aaaccactgt cctagcaccg tgtcc 25 <210> SEQ ID NO 119 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 119 aaacgaggct gttgggtcat tttcc 25 <210> SEQ ID NO 120 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 120 aaacagtggt caggccggcc aggcc 25 <210> SEQ ID NO 121 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 121 aaacgccagg ccttcagtgc tcagc 25 <210> SEQ ID NO 122 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 122 aaactcagtg ctcagtggaa accac 25 <210> SEQ ID NO 123 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 123 aaaccgaaag gactcctggc tatcc 25 <210> SEQ ID NO 124 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 124 aaacagtctg agcactggaa gcgcc 25 <210> SEQ ID NO 125 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 125 aaaccttccc tagtctgagc actgc 25 <210> SEQ ID NO 126 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 126 aaacggctct gaaggaggag gggcc 25 <210> SEQ ID NO 127 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 127 aaacggactc ctggctctga aggac 25 <210> SEQ ID NO 128 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 128 aaacagggtc aagctcggaa accac 25 <210> SEQ ID NO 129 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 129 aaacccccag cagatactct gcagc 25 <210> SEQ ID NO 130 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 130 aaacgcagat actctgcagg aacgc 25 <210> SEQ ID NO 131 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 131 tcccctccca gaaagacctg 20 <210> SEQ ID NO 132 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 132 tgggctccaa gcaatcctgg 20 <210> SEQ ID NO 133 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 133 gtggctcagg aggtacctgg 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 134 gagccacgaa aacagatcca 20 <210> SEQ ID NO 135 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 135 aagtgaacgg ggaagggagg 20 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 136 gacaaaagcc gaagtccagg 20 <210> SEQ ID NO 137 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 137 gtggttgata aacccacgtg 20 <210> SEQ ID NO 138 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 138 tgggaacagc cacagcaggg 20 <210> SEQ ID NO 139 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 139 gcaggggaac ggggatgcag 20 <210> SEQ ID NO 140 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 140 gagatggtgg acgaggaagg 20 <210> SEQ ID NO 141 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 141 gagatggctc caggaaatgg 20 <210> SEQ ID NO 142 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 142 taaggaatct gcctaacagg 20 <210> SEQ ID NO 143 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 143 tcaggagact aggaaggagg 20 <210> SEQ ID NO 144 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 144 tataaggtgg tcccagctcg 20 <210> SEQ ID NO 145 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 145 ctggaagatg ccatgacagg 20 <210> SEQ ID NO 146 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 146 gcacagacta gagaggtaag 20 <210> SEQ ID NO 147 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 147 acagactaga gaggtaaggg 20 <210> SEQ ID NO 148 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 148 gagaggtgac ccgaatccac 20 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 149 gcacaggccc cagaaggaga 20 <210> SEQ ID NO 150 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 150 ccggagagga cccagacacg 20 <210> SEQ ID NO 151 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 151 gagaggaccc agacacgggg 20 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 152 gcaacacagc agagagcaag 20 <210> SEQ ID NO 153 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 153 gaagagggag tggaggaaga 20 <210> SEQ ID NO 154 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 154 aagacggaac ctgaaggagg 20 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 155 agaaagcggc acaggcccag 20 <210> SEQ ID NO 156 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 156 gggaaacagt gggccagagg 20 <210> SEQ ID NO 157 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 157 gtccggactc aggagagaga 20 <210> SEQ ID NO 158 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 158 ggcacagcaa gggcactcgg 20 <210> SEQ ID NO 159 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 159 gaagagggga agtcgaggga 20 <210> SEQ ID NO 160 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 160 gggaatggta aggaggcctg 20 <210> SEQ ID NO 161 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 161 gcagagtggt cagcacagag 20 <210> SEQ ID NO 162 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 162 gcacagagtg gctaagccca 20 <210> SEQ ID NO 163 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 163 gacggggtgt cagcataggg 20 <210> SEQ ID NO 164 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 164 gcccagggcc aggaacgacg 20 <210> SEQ ID NO 165 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 165 ggtggagtcc agcacggcgc 20 <210> SEQ ID NO 166 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 166 acaggccgcc aggaactcgg 20 <210> SEQ ID NO 167 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 167 actaggaagt gtgtagcacc 20 <210> SEQ ID NO 168 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 168 atgaatagca gactgccccg 20 <210> SEQ ID NO 169 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 169 acacccctaa aagcacagtg 20 <210> SEQ ID NO 170 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 170 caaggagttc cagcaggtgg 20 <210> SEQ ID NO 171 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 171 aaggagttcc agcaggtggg 20 <210> SEQ ID NO 172 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 172 tggaaagagg agggaagagg 20 <210> SEQ ID NO 173 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 173 tcgaattcct aactgccccg 20 <210> SEQ ID NO 174 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 174 gacctgccca gcacaccctg 20 <210> SEQ ID NO 175 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 175 ggagcagctg cggcagtggg 20 <210> SEQ ID NO 176 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 176 gggagggaga gcttggcagg 20 <210> SEQ ID NO 177 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 177 gttacgtggc caagaagcag 20 <210> SEQ ID NO 178 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 178 gctgaacaga gaagagctgg 20 <210> SEQ ID NO 179 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 179 tctgagggtg gagggactgg 20 <210> SEQ ID NO 180 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 180 ggagaggtga gggacttggg 20 <210> SEQ ID NO 181 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 181 gtgaaccagg cagacaacga 20 <210> SEQ ID NO 182 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 182 caggtacctc ctgagccacg 20 <210> SEQ ID NO 183 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 183 gggggagtag gggcatgcag 20 <210> SEQ ID NO 184 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 184 gcaaatggcc agcaagggtg 20 <210> SEQ ID NO 185 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 185 caccgaatcg agaagcgact cgaca 25 <210> SEQ ID NO 186 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 186 caccggtccc tgggcgttgc cctgc 25 <210> SEQ ID NO 187 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 187 caccgccctg ggcgttgccc tgcag 25 <210> SEQ ID NO 188 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 188 caccgccgtg ggaagataaa ctaat 25 <210> SEQ ID NO 189 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 189 caccgtcccc tgcagggcaa cgccc 25 <210> SEQ ID NO 190 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 190 caccggtcga gtcgcttctc gatta 25 <210> SEQ ID NO 191 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 191 caccgctgct gcctcccgtc ttgta 25 <210> SEQ ID NO 192 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 192 caccggagtg ccgcaatacc tttat 25 <210> SEQ ID NO 193 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 193 caccgacact ttggtggtgc agcaa 25 <210> SEQ ID NO 194 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 194 caccgtctca aatggtataa aactc 25 <210> SEQ ID NO 195 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 195 caccgaatcc cgcccataat cgaga 25 <210> SEQ ID NO 196 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 196 caccgtcccg cccataatcg agaag 25 <210> SEQ ID NO 197 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 197 caccgcccat aatcgagaag cgact 25 <210> SEQ ID NO 198 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 198 caccggagaa gcgactcgac atgga 25 <210> SEQ ID NO 199 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 199 caccggaagc gactcgacat ggagg 25 <210> SEQ ID NO 200 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 200 caccggcgac tcgacatgga ggcga 25 <210> SEQ ID NO 201 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 201 aaactgtcga gtcgcttctc gattc 25 <210> SEQ ID NO 202 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 202 aaacgcaggg caacgcccag ggacc 25 <210> SEQ ID NO 203 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 203 aaacctgcag ggcaacgccc agggc 25 <210> SEQ ID NO 204 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 204 aaacattagt ttatcttccc acggc 25 <210> SEQ ID NO 205 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 205 aaacgggcgt tgccctgcag gggac 25 <210> SEQ ID NO 206 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 206 aaactaatcg agaagcgact cgacc 25 <210> SEQ ID NO 207 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 207 aaactacaag acgggaggca gcagc 25 <210> SEQ ID NO 208 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 208 aaacataaag gtattgcggc actcc 25 <210> SEQ ID NO 209 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 209 aaacttgctg caccaccaaa gtgtc 25 <210> SEQ ID NO 210 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 210 aaacgagttt tataccattt gagac 25 <210> SEQ ID NO 211 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 211 aaactctcga ttatgggcgg gattc 25 <210> SEQ ID NO 212 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 212 aaaccttctc gattatgggc gggac 25 <210> SEQ ID NO 213 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 213 aaacagtcgc ttctcgatta tgggc 25 <210> SEQ ID NO 214 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 214 aaactccatg tcgagtcgct tctcc 25 <210> SEQ ID NO 215 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 215 aaaccctcca tgtcgagtcg cttcc 25 <210> SEQ ID NO 216 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 216 aaactcgcct ccatgtcgag tcgcc 25 <210> SEQ ID NO 217 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 217 caccgacagg gttaatgtga agtcc 25 <210> SEQ ID NO 218 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 218 caccgtcccc ctctacattt aaagt 25 <210> SEQ ID NO 219 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 219 caccgcattt aaagttggtt taagt 25 <210> SEQ ID NO 220 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 220 caccgttaga aaatataaag aataa 25 <210> SEQ ID NO 221 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 221 caccgtaaat gcttactggt ttgaa 25 <210> SEQ ID NO 222 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 222 caccgtcctg ggtccagaaa aagat 25 <210> SEQ ID NO 223 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 223 caccgttggg tggtgagcat ctgtg 25 <210> SEQ ID NO 224 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 224 caccgcgggg agagtggaga aaaag 25 <210> SEQ ID NO 225 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 225 caccggttaa aactctttag acaac 25 <210> SEQ ID NO 226 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 226 caccggaaaa tccccactaa gatcc 25 <210> SEQ ID NO 227 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 227 aaacggactt cacattaacc ctgtc 25 <210> SEQ ID NO 228 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 228 aaacacttta aatgtagagg gggac 25 <210> SEQ ID NO 229 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 229 aaacacttaa accaacttta aatgc 25 <210> SEQ ID NO 230 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 230 aaacttattc tttatatttt ctaac 25 <210> SEQ ID NO 231 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 231 aaacttcaaa ccagtaagca tttac 25 <210> SEQ ID NO 232 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 232 aaacatcttt ttctggaccc aggac 25 <210> SEQ ID NO 233 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 233 aaaccacaga tgctcaccac ccaac 25 <210> SEQ ID NO 234 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 234 aaaccttttt ctccactctc cccgc 25 <210> SEQ ID NO 235 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 235 aaacgttgtc taaagagttt taacc 25 <210> SEQ ID NO 236 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 236 aaacggatct tagtggggat tttcc 25 <210> SEQ ID NO 237 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 237 agtagcagta atgaagctgg 20 <210> SEQ ID NO 238 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 238 atacccagac gagaaagctg 20 <210> SEQ ID NO 239 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 239 tacccagacg agaaagctga 20 <210> SEQ ID NO 240 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 240 ggtggtgagc atctgtgtgg 20 <210> SEQ ID NO 241 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 241 aaatgagaag aagaggcaca 20 <210> SEQ ID NO 242 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 242 cttgtggcct gggagagctg 20 <210> SEQ ID NO 243 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 243 gctgtagaag gagacagagc 20 <210> SEQ ID NO 244 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 244 gagctggttg ggaagacatg 20 <210> SEQ ID NO 245 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 245 ctggttggga agacatgggg 20 <210> SEQ ID NO 246 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 246 cgtgaggatg ggaaggaggg 20 <210> SEQ ID NO 247 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 247 atgcagagtc agcagaactg 20 <210> SEQ ID NO 248 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 248 aagacatcaa gcacagaagg 20 <210> SEQ ID NO 249 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 249 tcaagcacag aaggaggagg 20 <210> SEQ ID NO 250 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 250 aaccgtcaat aggcaaaggg 20 <210> SEQ ID NO 251 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 251 ccgtatttca gactgaatgg 20 <210> SEQ ID NO 252 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 252 gagaggacag gtgctacagg 20 <210> SEQ ID NO 253 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 253 aaccaaggaa gggcaggagg 20 <210> SEQ ID NO 254 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 254 gacctctggg tggagacaga 20 <210> SEQ ID NO 255 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 255 cagatgacca tgacaagcag 20 <210> SEQ ID NO 256 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 256 aacaccagtg agtagagcgg 20 <210> SEQ ID NO 257 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 257 aggaccttga agcacagaga 20 <210> SEQ ID NO 258 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 258 tacagaggca gactaaccca 20 <210> SEQ ID NO 259 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 259 acagaggcag actaacccag 20 <210> SEQ ID NO 260 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 260 taaatgacgt gctagacctg 20 <210> SEQ ID NO 261 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 261 agtaaccact caggacaggg 20 <210> SEQ ID NO 262 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 262 accacaaaac agaaacacca 20 <210> SEQ ID NO 263 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 263 gtttgaagac aagcctgagg 20 <210> SEQ ID NO 264 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 264 gctgaacccc aaaagacagg 20 <210> SEQ ID NO 265 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 265 gcagctgaga cacacaccag 20 <210> SEQ ID NO 266 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 266 aggacacccc aaagaagctg 20 <210> SEQ ID NO 267 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 267 ggacacccca aagaagctga 20 <210> SEQ ID NO 268 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 268 ccagtgcaat ggacagaaga 20 <210> SEQ ID NO 269 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 269 agaagaggga gcctgcaagt 20 <210> SEQ ID NO 270 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 270 gtgtttgggc cctagagcga 20 <210> SEQ ID NO 271 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 271 catgtgcctg gtgcaatgca 20 <210> SEQ ID NO 272 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 272 tacaaagagg aagataagtg 20 <210> SEQ ID NO 273 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 273 gtcacagaat acaccactag 20 <210> SEQ ID NO 274 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 274 gggttaccct ggacatggaa 20 <210> SEQ ID NO 275 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 275 catggaaggg tattcactcg 20 <210> SEQ ID NO 276 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 276 agagtggcct agacaggctg 20 <210> SEQ ID NO 277 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 277 catgctggac agctcggcag 20 <210> SEQ ID NO 278 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 278 agtgaaagaa gagaaaattc 20 <210> SEQ ID NO 279 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 279 tggtaagtct aagaaaccta 20 <210> SEQ ID NO 280 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 280 cccacagcct aaccacccta 20 <210> SEQ ID NO 281 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 281 aatatttcaa agccctaggg 20 <210> SEQ ID NO 282 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 282 gcactcggaa cagggtctgg 20 <210> SEQ ID NO 283 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 283 agataggagc tccaacagtg 20 <210> SEQ ID NO 284 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 284 aagttagagc agccaggaaa 20 <210> SEQ ID NO 285 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 285 tagagcagcc aggaaaggga 20 <210> SEQ ID NO 286 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 286 tgaataccct tccatgtcca 20 <210> SEQ ID NO 287 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 287 cctgcattgc accaggcaca 20 <210> SEQ ID NO 288 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 288 tctagggccc aaacacacct 20 <210> SEQ ID NO 289 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 289 tccctccatc tatcaaaagg 20 <210> SEQ ID NO 290 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 290 agccctgaga cagaagcagg 20 <210> SEQ ID NO 291 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 291 gccctgagac agaagcaggt 20 <210> SEQ ID NO 292 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 292 aggagatgca gtgatacgca 20 <210> SEQ ID NO 293 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 293 acaataccaa gggtatccgg 20 <210> SEQ ID NO 294 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 294 tgataaagaa aacaaagtga 20 <210> SEQ ID NO 295 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 295 aaagaaaaca aagtgaggga 20 <210> SEQ ID NO 296 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 296 gtggcaagtg gagaaattga 20 <210> SEQ ID NO 297 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 297 caagtggaga aattgaggga 20 <210> SEQ ID NO 298 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 298 gtggtgatga ttgcagctgg 20 <210> SEQ ID NO 299 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 299 ctatgtgcct gacacacagg 20 <210> SEQ ID NO 300 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 300 gggttggacc aggaaagagg 20 <210> SEQ ID NO 301 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 301 gatgcctgga aaaggaaaga 20 <210> SEQ ID NO 302 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 302 tagtatgcac ctgcaagagg 20 <210> SEQ ID NO 303 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 303 tatgcacctg caagaggcgg 20 <210> SEQ ID NO 304 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 304 aggggaagaa gagaagcaga 20 <210> SEQ ID NO 305 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 305 gctgaatcaa gagacaagcg 20 <210> SEQ ID NO 306 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 306 aagcaaataa atctcctggg 20 <210> SEQ ID NO 307 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 307 agatgagtgc tagagactgg 20 <210> SEQ ID NO 308 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 308 ctgatggttg agcacagcag 20 <210> SEQ ID NO 309 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 309 caaatggcca gcaagggtgg 20 <210> SEQ ID NO 310 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 310 gcagaacctg aggatatgga 20 <210> SEQ ID NO 311 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 311 aatacacaga atgaaaatag 20 <210> SEQ ID NO 312 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 312 ctggtgacta gaataggcag 20 <210> SEQ ID NO 313 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 313 tggtgactag aataggcagt 20 <210> SEQ ID NO 314 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 314 taaaagaatg tgaaaagatg 20 <210> SEQ ID NO 315 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 315 tcaggagttc aagaccaccc 20 <210> SEQ ID NO 316 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 316 tgtagtccca gttatgcagg 20 <210> SEQ ID NO 317 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 317 gggttcacac cacaaatgca 20 <210> SEQ ID NO 318 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 318 ggcaaatggc cagcaagggt 20 <210> SEQ ID NO 319 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 319 agaaaccaat cccaaagcaa 20 <210> SEQ ID NO 320 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 320 gccaaggaca ccaaaaccca 20 <210> SEQ ID NO 321 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 321 agtggtgata aggcaacagt 20 <210> SEQ ID NO 322 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 322 cctgagacag aagtattaag 20 <210> SEQ ID NO 323 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 323 aaggtcacac aatgaatagg 20 <210> SEQ ID NO 324 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 324 caccatacta gggaagaaga 20 <210> SEQ ID NO 325 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 325 aataccctgc ccttagtggg 20 <210> SEQ ID NO 326 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 326 ttagtggggg gtggagtggg 20 <210> SEQ ID NO 327 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 327 caataccctg cccttagtgg 20 <210> SEQ ID NO 328 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 328 gtggggggtg gagtgggggg 20 <210> SEQ ID NO 329 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 329 ggggggtgga gtggggggtg 20 <210> SEQ ID NO 330 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 330 ggggtggagt ggggggtggg 20 <210> SEQ ID NO 331 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 331 gggtggagtg gggggtgggg 20 <210> SEQ ID NO 332 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 332 gggggtgggg aaagacatcg 20 <210> SEQ ID NO 333 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 333 gcagctgtga attctgatag 20 <210> SEQ ID NO 334 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 334 gagatcagag aaaccagatg 20 <210> SEQ ID NO 335 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 335 tctatactga ttgcagccag 20 <210> SEQ ID NO 336 <211> LENGTH: 1722 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 336 atggcgcaac actcagatta ctccgacgat gaattttgtg ctgacaaact gtccaattat 60 tcatgcgata gcgacctcga aaacgcttcc acgtctgatg aagatagcag cgatgatgaa 120 gtaatggtga ggcctcgcac cctccgccgt cgccgcatca gctcttcgag ctctgattct 180 gaatccgata ttgagggtgg ccgcgaggag tggtcccacg tagacaatcc gccggtgctg 240 gaggacttcc taggccacca aggtctgaac actgacgcag taatcaacaa tatcgaagat 300 gcagttaaac tgtttatcgg tgacgatttc ttcgagtttc tggtggagga atctaaccgg 360 tactataacc agaatcgtaa taacttcaag ctctctaaaa agtctctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctc ggtctgatcg ttctgatggg ccaagttcgc 480 aaggatcgtc gtgacgacta ttggactacc gaaccgtgga cggaaactcc atactttggc 540 aagaccatga ctcgtgaccg tttccgtcag atctggaagg cctggcactt caataacaac 600 gctgacattg tcaacgagtc tgatcgtctg tgtaaggttc gccctgtgct ggattacttc 660 gttccaaaat tcattaacat ttacaaacca catcagcagc tgtccctgga tgagggcatc 720 gtgccgtggc gcggccgcct gttcttccgt gtctataatg ctggcaagat tgtgaagtac 780 ggtatcctgg ttcgcctgct gtgcgaaagc gacactggct acatctgtaa catggagatc 840 tactgcggcg agggcaaacg tctcctcgaa actatccaga ccgtcgtgtc tccatacacg 900 gattcctggt atcatattta catggataac tattataaca gcgtggctaa ctgtgaagct 960 ctgatgaaaa ataagttccg tatttgcggt actatccgta agaatcgtgg aattccgaaa 1020 gatttccaga ccatctccct gaaaaagggt gaaactaagt tcattcgcaa aaacgacatc 1080 ctcctgcaag tctggcagtc taaaaagcct gtatatctga tctcatctat tcacagcgct 1140 gaaatggaag aatctcagaa cattgatcgc acctccaaga aaaagatcgt caaaccgaat 1200 gcattgattg attacaacaa gcacatgaag ggcgttgatc gtgctgacca gtacctgtct 1260 tattactcta tcctgcgccg tactgtgaag tggactaaac gtctcgctat gtacatgatt 1320 aattgtgcgc tgttcaattc ttacgctgtg tataaaagcg tgcgtcagcg caaaatgggc 1380 tttaaaatgt tcctgaagca gacggctatt cactggctga ccgacgatat tccggaagat 1440 atggacattg tcccggatct ccagccggta ccgagcacca gcggtatgcg tgctaaacct 1500 ccgactagtg atccgccttg ccgtctgtct atggatatgc gtaagcatac cctgcaggca 1560 attgtgggct ctggcaaaaa gaaaaatatc ctgcgtcgtt gccgcgtatg ctctgtacac 1620 aaactgcgtt ctgagactcg ttatatgtgt aaattttgca atattccact ccacaagggt 1680 gcgtgcttcg agaagtacca tacgctgaag aactatctcg ag 1722 <210> SEQ ID NO 337 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 337 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 338 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 338 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 339 <211> LENGTH: 1716 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 339 atgtcgcagc attcagacta tactcatgat gagttttgtg cagacaagtt gtccaattat 60 tcttgtgata gcgatcttga aaatgcgagt acaagtgatg aagattctag tgatgatgaa 120 gtaatggtgc gtcccaggac attgaggcga cgaagaattt cgagctccag ctctgactca 180 gagtcagata tagaaggcgg gagagaagaa tggtcgcatg ttgataatcc accggtctta 240 gaagattttt tagggcatca aggattaaac acagatgctg ttataaataa tatagaagat 300 gccgtgaaat tatttatcgg agatgatttt tttgaatttc ttgtagagga gtcaaacagg 360 tattataatc aaaataggaa taatttcaaa ctttcaaaaa aaagcctaaa gtggaaagat 420 ataacccctc aagagatgaa gaagttttta gggttaattg ttctcatggg acaggtgcgc 480 aaagatagaa gagatgacta ttggaccacg gagccatgga cggagacgcc atattttggt 540 aaaacgatga cgagagacag gttccgacag atatggaaag cttggcactt caataataat 600 gcggatatcg taaatgaatc agatagactt tgcaaagtga gaccagtact agattatttt 660 gtgcctaaat ttataaatat ttacaaacct catcagcaat tatcactaga tgaagggatc 720 gtaccttgga ggggaagatt attctttagg gtatataatg ctggcaagat cgttaaatat 780 ggaatattgg ttcgtttgtt gtgcgaaagt gatacaggat atatctgtaa catggaaatt 840 tattgcggcg aaggaaagcg attattggaa acgatacaaa cagtagtgtc tccatacact 900 gattcgtggt accatatata tatggacaat tattataata gcgtcgcaaa ttgtgaagca 960 cttatgaaaa acaaattcag aatatgtgga acaatccgga aaaatcgagg tatacctaaa 1020 gattttcaaa caatttcttt gaaaaaaggt gaaacaaaat ttataaggaa aaatgatata 1080 ttgttacaag tgtggcaatc aaaaaagcct gtatacctga tttcttcgat tcattctgcg 1140 gagatggaag aaagtcagaa tattgacaga acatcaaaaa agaaaattgt caaaccgaat 1200 gcactcattg actacaataa acatatgaaa ggtgttgacc gggccgacca atacctttca 1260 tattattcga tattgcggag gacggtcaaa tggacaaaaa ggttggcaat gtatatgata 1320 aattgcgcat tatttaattc ttatgcagtt tacaaatcag tgaggcaaag aaaaatgggt 1380 tttaaaatgt ttttgaaaca aacagctatc cactggttga cggatgatat tccagaggac 1440 atggacattg ttccagacct tcaaccagta ccgtctactt ctggaatgcg ggctaaacca 1500 cctacatctg atccaccatg caggctatcg atggacatga gaaagcatac gttacaggca 1560 attgtcggaa gtggaaaaaa gaaaaacatt ttgagaaggt gtcgcgtatg ttccgttcat 1620 aaattgcgca gtgagacacg ctacatgtgc aaattttgca atatacctct acataaaggg 1680 gcgtgttttg aaaaatatca tacgctaaaa aactat 1716 <210> SEQ ID NO 340 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 340 Met Ala Gln His Ser Asp Tyr Pro Asp Asp Glu Phe Arg Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Lys Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 341 <211> LENGTH: 574 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 341 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr Leu Glu 565 570 <210> SEQ ID NO 342 <400> SEQUENCE: 342 000 <210> SEQ ID NO 343 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 343 Met Ser Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Lys Thr Met Thr Arg Asp Arg Phe 115 120 125 Arg Gln Ile Trp Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val 130 135 140 Asn Glu Ser Asp Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe 145 150 155 160 Val Pro Lys Phe Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu 165 170 175 Asp Glu Gly Ile Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr 180 185 190 Asn Ala Gly Lys Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys 195 200 205 Glu Ser Asp Thr Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu 210 215 220 Gly Lys Arg Leu Leu Glu Thr Ile Gln Thr Trp Ser Pro Tyr Thr Asp 225 230 235 240 Ser Trp Tyr His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn 245 250 255 Cys Glu Ala Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg 260 265 270 Lys Asn Arg Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys 275 280 285 Gly Glu Thr Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp 290 295 300 Gln Ser Lys Lys Pro Val Tyr Leu Ile Ser Ser His Ser Ala Glu Met 305 310 315 320 Glu Glu Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys 325 330 335 Pro Asn Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg 340 345 350 Ala Asp Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Trp Lys Trp 355 360 365 Thr Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser 370 375 380 Tyr Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met 385 390 395 400 Phe Leu Lys Gln Thr Ala His Trp Leu Thr Asp Asp Ile Pro Glu Asp 405 410 415 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 420 425 430 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 435 440 445 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 450 455 460 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 465 470 475 480 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 485 490 495 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn 500 505 <210> SEQ ID NO 344 <211> LENGTH: 153 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 344 cacttggatt gcgggaaacg agttaagtcg gctcgcgtga attgcgcgta ctccgcggga 60 gccgtcttaa ctcggttcat atagatttgc ggtggagtgc gggaaacgtg taaactcggg 120 ccgattgtaa ctgcgtatta ccaaatattt gtt 153 <210> SEQ ID NO 345 <211> LENGTH: 158 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 345 cacttgggtt gcgggaaacg agttaagtcg gctcgcgtga attgcgcgta ctccgcggga 60 gccgtcttaa actcggttca tatagatttg cggtggagtg cgggaaacgt tgtaaactcg 120 ggccgattgt aactgcgtat taccaaatat ttcatttc 158 <210> SEQ ID NO 346 <211> LENGTH: 181 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 346 aaatgtctgt gattgaataa attttcattt tttacacaag aaaccgaaaa tttcatttca 60 atcgaaccca tacttcaaaa gatataggca ttttaaacta actctgattt tgcgcgggaa 120 acctaaataa ttgcccgcgc catcttatat tttggcggga aattcacccg acaccgtagt 180 g 181 <210> SEQ ID NO 347 <211> LENGTH: 136 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 347 aaacgttgta aactcgggcc gattgtaact gcgtattacc aaatatttca tttcaatcga 60 acccatactt aaaagatata ggcattttaa cgcgccatct tatattttgg cgggaaattc 120 acccgacacc gtagtg 136 <210> SEQ ID NO 348 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(6) <223> OTHER INFORMATION: Xaa can be any naturally occurring amino acid; SEQ ID NO: 348 corresponds to the sequence K(K/R)X(K/R) <400> SEQUENCE: 348 Lys Lys Arg Xaa Lys Arg 1 5 <210> SEQ ID NO 349 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(7) <223> OTHER INFORMATION: Xaa can be any naturally occurring amino acid; SEQ ID NO: 349 corresponds to the sequence (K/R)(K/R)X10- 12(K/R)3/5 <400> SEQUENCE: 349 Lys Arg Lys Arg Xaa Lys Arg 1 5 <210> SEQ ID NO 350 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 350 Pro Ala Ala Lys Arg Val Lys Leu Asp 1 5 <210> SEQ ID NO 351 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 351 Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys 1 5 10 15 <210> SEQ ID NO 352 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 352 Pro Lys Lys Lys Arg Lys Val 1 5 <210> SEQ ID NO 353 <211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 353 Asp Pro Lys Lys Lys Arg Lys Val Asp Pro Lys Lys Lys Arg Lys Val 1 5 10 15 Asp Pro Lys Lys Lys Arg Lys Val 20 <210> SEQ ID NO 354 <400> SEQUENCE: 354 000 <210> SEQ ID NO 355 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 355 Asn His Asn His His Asp His Asp Asn His Asn His His Asp His Asp 1 5 10 15 Asn Gly Asn His Asn Ile His Asp His Asp Asn Ile His Asp Asn Gly 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 356 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 356 Asn His Asn Ile Asn Ile Asn His Asn His His Asp His Asp Asn Gly 1 5 10 15 Asn His Asn His His Asp His Asp Asn His Asn His His Asp His Asp 20 25 30 Asn Gly Asn His 35 <210> SEQ ID NO 357 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 357 Asn His Asn Ile Asn His His Asp Asn Ile His Asp Asn Gly Asn His 1 5 10 15 Asn Ile Asn Ile Asn His Asn His His Asp His Asp Asn Gly Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 358 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 358 His Asp His Asp Asn Ile His Asp Asn Gly Asn His Asn Ile Asn His 1 5 10 15 His Asp Asn Ile His Asp Asn Gly Asn His Asn Ile Asn Ile Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 359 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 359 Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp His Asp Asn Ile 1 5 10 15 His Asp Asn Gly Asn His Asn Ile Asn His His Asp Asn Ile His Asp 20 25 30 Asn Gly Asn His 35 <210> SEQ ID NO 360 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 360 Asn His Asn His Asn His Asn His Asn Ile Asn Ile Asn Ile Asn Ile 1 5 10 15 Asn Gly Asn His Asn Ile His Asp His Asp His Asp Asn Ile Asn Ile 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 361 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 361 Asn Ile Asn His Asn His Asn Ile His Asp Asn Ile Asn His Asn Gly 1 5 10 15 Asn His Asn His Asn His Asn His Asn Ile Asn Ile Asn Ile Asn Ile 20 25 30 Asn Gly Asn His 35 <210> SEQ ID NO 362 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 362 His Asp His Asp Asn Ile Asn His Asn His Asn His Asn Ile His Asp 1 5 10 15 Asn Ile His Asp Asn His Asn His Asn Gly Asn His His Asp Asn Gly 20 25 30 Asn Ile Asn His 35 <210> SEQ ID NO 363 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 363 His Asp Asn Ile Asn His Asn Ile Asn His His Asp His Asp Asn Ile 1 5 10 15 Asn His Asn His Asn Ile Asn His Asn Gly His Asp His Asp Asn Gly 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 364 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 364 His Asp His Asp Asn Gly Asn Gly His Asp Asn Ile Asn His Asn Ile 1 5 10 15 Asn His His Asp His Asp Asn Ile Asn His Asn His Asn Ile Asn His 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 365 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 365 His Asp His Asp Asn Gly His Asp His Asp Asn Gly Asn Gly His Asp 1 5 10 15 Asn Ile Asn His Asn Ile Asn His His Asp His Asp Asn Ile Asn His 20 25 30 Asn His Asn Ile 35 <210> SEQ ID NO 366 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 366 His Asp His Asp Asn Ile Asn His His Asp His Asp His Asp His Asp 1 5 10 15 Asn Gly His Asp His Asp Asn Gly His Asp His Asp Asn Gly Asn Gly 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 367 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 367 His Asp His Asp Asn His Asn Ile Asn His His Asp Asn Gly Asn Gly 1 5 10 15 Asn His Asn Ile His Asp His Asp His Asp Asn Gly Asn Gly Asn His 20 25 30 Asn His Asn Ile 35 <210> SEQ ID NO 368 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 368 Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp His Asp Asn His 1 5 10 15 Asn Ile Asn His His Asp Asn Gly Asn Gly Asn His Asn Ile His Asp 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 369 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 369 Asn His Asn His Asn His Asn His Asn Gly Asn His Asn His Asn Gly 1 5 10 15 Asn Gly Asn Gly His Asp His Asp Asn His Asn Ile Asn His His Asp 20 25 30 Asn Gly Asn Gly 35 <210> SEQ ID NO 370 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 370 His Asp Asn Gly Asn His His Asp Asn Gly Asn His Asn His Asn His 1 5 10 15 Asn His Asn Gly Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp 20 25 30 His Asp Asn His 35 <210> SEQ ID NO 371 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 371 Asn His His Asp Asn Ile Asn His Asn Ile Asn His Asn Gly Asn Ile 1 5 10 15 Asn Gly His Asp Asn Gly Asn His His Asp Asn Gly Asn His Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 372 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 372 His Asp His Asp Asn Ile Asn Ile Asn Gly His Asp His Asp His Asp 1 5 10 15 His Asp Asn Gly His Asp Asn Ile Asn His Asn Gly 20 25 <210> SEQ ID NO 373 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 373 His Asp Asn Ile Asn His Asn Gly Asn His His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn His Asn Gly Asn His Asn His Asn Ile Asn Ile 20 25 30 <210> SEQ ID NO 374 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 374 Asn His Asn Ile Asn Ile Asn Ile His Asp Asn Ile Asn Gly His Asp 1 5 10 15 His Asp Asn His Asn His His Asp Asn His Asn Ile His Asp Asn Gly 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 375 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 375 His Asp Asn His His Asp His Asp His Asp His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn Ile Asn Ile Asn Gly His Asp Asn Gly Asn Gly Asn Ile 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 376 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 376 His Asp Asn Ile Asn Ile Asn Ile Asn Gly His Asp Asn Gly Asn Gly 1 5 10 15 Asn Ile His Asp Asn Ile Asn His His Asp Asn Gly Asn His His Asp 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 377 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 377 His Asp Asn Gly Asn Gly Asn Ile His Asp Asn Ile Asn His His Asp 1 5 10 15 Asn Gly Asn His His Asp Asn Gly His Asp Asn Ile His Asp Asn Gly 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 378 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 378 Asn Ile His Asp Asn Ile Asn His His Asp Asn Gly Asn His His Asp 1 5 10 15 Asn Gly His Asp Asn Ile His Asp Asn Gly His Asp His Asp His Asp 20 25 30 His Asp Asn Gly 35 <210> SEQ ID NO 379 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 379 Asn His His Asp Asn Gly His Asp Asn Ile His Asp Asn Gly His Asp 1 5 10 15 His Asp His Asp His Asp Asn Gly Asn His His Asp Asn Ile Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 380 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 380 His Asp His Asp His Asp His Asp Asn Gly Asn His His Asp Asn Ile 1 5 10 15 Asn His Asn His Asn His His Asp Asn Ile Asn Ile His Asp Asn His 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 381 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 381 Asn His His Asp Asn Ile Asn His Asn His Asn His His Asp Asn Ile 1 5 10 15 Asn Ile His Asp Asn His His Asp His Asp His Asp Asn Ile Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 382 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 382 His Asp Asn Gly His Asp Asn His Asn Ile Asn Gly Asn Gly Asn Ile 1 5 10 15 Asn Gly Asn His Asn His Asn His His Asp Asn His Asn His Asn His 20 25 30 Asn Ile Asn Gly 35 <210> SEQ ID NO 383 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 383 His Asp Asn His His Asp Asn Gly Asn Gly His Asp Asn Gly His Asp 1 5 10 15 Asn His Asn Ile Asn Gly Asn Gly Asn Ile Asn Gly Asn His Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 384 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 384 Asn His Asn Gly His Asp Asn His Asn Ile Asn His Asn Gly His Asp 1 5 10 15 Asn His His Asp Asn Gly Asn Gly His Asp Asn Gly His Asp Asn His 20 25 30 Asn Ile Asn Gly 35 <210> SEQ ID NO 385 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 385 His Asp His Asp Asn Ile Asn Gly Asn His Asn Gly His Asp Asn His 1 5 10 15 Asn Ile Asn His Asn Gly His Asp Asn His His Asp Asn Gly Asn Gly 20 25 30 His Asp Asn Gly 35 <210> SEQ ID NO 386 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 386 His Asp Asn His His Asp His Asp Asn Gly His Asp His Asp Asn Ile 1 5 10 15 Asn Gly Asn His Asn Gly His Asp Asn His Asn Ile Asn His Asn Gly 20 25 30 His Asp Asn His 35 <210> SEQ ID NO 387 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 387 His Asp Asn His Asn Gly His Asp Asn Ile Asn Gly His Asp Asn His 1 5 10 15 His Asp His Asp Asn Gly His Asp His Asp Asn Ile Asn Gly Asn His 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 388 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 388 Asn His Asn Ile Asn Gly His Asp Asn Gly His Asp Asn His Asn Gly 1 5 10 15 His Asp Asn Ile Asn Gly His Asp Asn His His Asp His Asp Asn Gly 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 389 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 389 Asn His His Asp Asn Gly Asn Gly His Asp Asn Ile Asn His His Asp 1 5 10 15 Asn Gly Asn Gly His Asp His Asp Asn Gly Asn Ile 20 25 <210> SEQ ID NO 390 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 390 His Asp Asn Gly Asn Lys Asn Gly Asn His Asn Ile Asn Gly His Asp 1 5 10 15 Asn Ile Asn Gly Asn His His Asp His Asp Asn Ile 20 25 <210> SEQ ID NO 391 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 391 Asn Ile His Asp Asn Ile Asn Asn Asn Gly Asn Asn Asn Asn Asn Gly 1 5 10 15 Asn Ile His Asp Asn Ile His Asp Asn Ile His Asp His Asp Asn Gly 20 25 30 <210> SEQ ID NO 392 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 392 His Asp His Asp Asn Ile His Asp His Asp His Asp His Asp His Asp 1 5 10 15 His Asp Asn Ile His Asp Asn Gly Asn Ile Asn Ile Asn Asn 20 25 30 <210> SEQ ID NO 393 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 393 His Asp Asn Ile Asn Gly Asn Gly Asn Asn Asn Asn His Asp His Asp 1 5 10 15 Asn Asn Asn Asn Asn Asn His Asp Asn Ile His Asp 20 25 <210> SEQ ID NO 394 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 394 Asn Asn His Asp Asn Gly Asn Gly Asn Asn Asn Ile Asn Ile His Asp 1 5 10 15 His Asp His Asp Asn Ile Asn Asn Asn Asn Asn Ile Asn Asn Asn Ile 20 25 30 <210> SEQ ID NO 395 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 395 Asn Ile His Asp Asn Ile His Asp His Asp His Asp Asn Asn Asn Ile 1 5 10 15 Asn Gly His Asp His Asp Asn Ile His Asp Asn Gly Asn Asn Asn Asn 20 25 30 Asn Asn <210> SEQ ID NO 396 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 396 Asn Asn His Asp Asn Gly Asn Asn His Asp Asn Ile Asn Gly His Asp 1 5 10 15 Asn Ile Asn Ile His Asp His Asp His Asp His Asp 20 25 <210> SEQ ID NO 397 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 397 Asn Asn Asn Asn His Asp Asn Ile His Asp Asn Asn Asn Ile Asn Ile 1 5 10 15 Asn Ile His Asp Asn Ile His Asp His Asp His Asp Asn Gly His Asp 20 25 30 His Asp <210> SEQ ID NO 398 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 398 Asn Asn Asn Asn Asn Gly Asn Asn Asn Asn His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn Gly Asn Asn His Asp His Asp Asn Gly Asn Asn 20 25 30 <210> SEQ ID NO 399 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 399 Asn Asn Asn Ile Asn Gly Asn Gly Asn Gly Asn Asn His Asp Asn Ile 1 5 10 15 His Asp Asn Ile Asn Asn His Asp Asn Gly His Asp Asn Ile Asn Gly 20 25 30 <210> SEQ ID NO 400 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 400 Asn Ile Asn Ile Asn His His Asp Asn Gly His Asp Asn Gly Asn His 1 5 10 15 Asn Ile Asn His Asn His Asn Ile Asn His His Asp 20 25 <210> SEQ ID NO 401 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 401 His Asp His Asp His Asp Asn Gly Asn Ile Asn Lys His Asp Asn Gly 1 5 10 15 Asn His Asn Gly His Asp His Asp His Asp His Asp 20 25 <210> SEQ ID NO 402 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 402 Asn His His Asp His Asp Asn Gly Asn Ile Asn His His Asp Asn Ile 1 5 10 15 Asn Gly Asn His His Asp Asn Gly Asn Ile Asn His 20 25 <210> SEQ ID NO 403 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 403 Asn Ile Asn Gly Asn His Asn His Asn His His Asp Asn Gly Asn Gly 1 5 10 15 His Asp Asn Ile His Asp Asn His Asn His Asn Ile Asn Gly 20 25 30 <210> SEQ ID NO 404 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 404 Asn His Asn Ile Asn Ile Asn Ile His Asp Asn Gly Asn Ile Asn Gly 1 5 10 15 Asn His His Asp His Asp Asn Gly Asn His His Asp 20 25 <210> SEQ ID NO 405 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 405 Asn His His Asp Asn Ile His Asp His Asp Asn Ile Asn Gly Asn Gly 1 5 10 15 Asn His His Asp Asn Gly His Asp His Asp His Asp 20 25 <210> SEQ ID NO 406 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 406 Asn His Asn Ile His Asp Asn Ile Asn Gly Asn His His Asp Asn Ile 1 5 10 15 Asn Ile His Asp Asn Gly His Asp Asn Ile Asn His 20 25 <210> SEQ ID NO 407 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 407 Asn Ile His Asp Asn Ile His Asp His Asp Asn Ile His Asp Asn Gly 1 5 10 15 Asn Ile Asn His Asn His Asn His Asn His Asn Gly 20 25 <210> SEQ ID NO 408 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 408 Asn His Asn Gly His Asp Asn Gly Asn His His Asp Asn Gly Asn Ile 1 5 10 15 Asn His Asn Ile His Asp Asn Ile Asn His Asn His 20 25 <210> SEQ ID NO 409 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 409 Asn His Asn His His Asp His Asp Asn Gly Asn Ile Asn His Asn Ile 1 5 10 15 His Asp Asn Ile Asn His Asn His His Asp Asn Gly Asn His 20 25 30 <210> SEQ ID NO 410 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 410 Asn His Asn Ile Asn His Asn His His Asp Asn Ile Asn Gly Asn Gly 1 5 10 15 His Asp Asn Gly Asn Gly Asn Ile Asn Gly His Asp Asn His 20 25 30 <210> SEQ ID NO 411 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 411 Asn Asn His Asp His Asp Asn Gly Asn Asn Asn Asn Asn Ile Asn Ile 1 5 10 15 Asn Ile His Asp Asn Asn Asn Gly Asn Gly His Asp His Asp 20 25 30 <210> SEQ ID NO 412 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 412 Asn Asn Asn Gly Asn Asn His Asp Asn Gly His Asp Asn Gly Asn Asn 1 5 10 15 Asn Ile His Asp Asn Ile Asn Ile Asn Gly Asn Ile 20 25 <210> SEQ ID NO 413 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 413 Asn Asn Asn Gly Asn Gly Asn Gly Asn Gly Asn Asn His Asp Asn Ile 1 5 10 15 Asn Asn His Asp His Asp Asn Gly His Asp His Asp 20 25 <210> SEQ ID NO 414 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 414 Asn Ile His Asp Asn Ile Asn Asn His Asp Asn Gly Asn Asn Asn Gly 1 5 10 15 Asn Asn Asn Asn Asn Ile Asn Ile His Asp Asn Asn Asn Gly 20 25 30 <210> SEQ ID NO 415 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 415 His Asp Asn Ile Asn Ile Asn Asn Asn Ile His Asp His Asp Asn Asn 1 5 10 15 Asn Ile Asn Asn His Asp Asn Ile His Asp Asn Gly Asn Asn His Asp 20 25 30 Asn Gly Asn Asn 35 <210> SEQ ID NO 416 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 416 His Asp Asn Gly Asn Ile Asn Gly His Asp His Asp His Asp Asn Ile 1 5 10 15 Asn Ile Asn Ile Asn Ile His Asp Asn Gly His Asp Asn Gly 20 25 30 <210> SEQ ID NO 417 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 417 Asn His Asn Ile Asn Ile Asn Ile Asn Ile Asn Ile His Asp Asn Gly 1 5 10 15 Asn Ile Asn Gly Asn His Asn Gly Asn Ile Asn Gly 20 25 <210> SEQ ID NO 418 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 418 Asn Ile Asn His Asn His His Asp Asn Ile Asn His Asn His His Asp 1 5 10 15 Asn Gly Asn His Asn His Asn Gly Asn Gly Asn His Asn Ile 20 25 30 <210> SEQ ID NO 419 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 419 His Asp Asn Ile Asn Ile Asn Gly Asn Ile His Asp Asn Ile Asn Ile 1 5 10 15 His Asp His Asp Asn Ile His Asp Asn Asn His Asp 20 25 <210> SEQ ID NO 420 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 420 Asn Ile Asn Gly Asn Asn Asn Ile His Asp Asn Asn Asn Asn Asn Ile 1 5 10 15 His Asp Asn Gly His Asp Asn Ile Asn Ile His Asp Asn Gly 20 25 30 <210> SEQ ID NO 421 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 421 His Asp Asn Ile His Asp Asn Ile Asn Ile His Asp Asn Ile Asn Gly 1 5 10 15 Asn Gly Asn Gly Asn Asn Asn Gly Asn Ile Asn Ile 20 25 <210> SEQ ID NO 422 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 422 Asn Ile Asn Gly Asn Gly Asn Gly His Asp His Asp Asn Ile Asn Asn 1 5 10 15 Asn Gly Asn Asn His Asp Asn Ile His Asp Asn Ile 20 25 <210> SEQ ID NO 423 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 423 ggcggatctg gcggtagtgc tgagtattgt ctgagttacg aaacggaaat actcacggtt 60 gagtatgggc ttcttccaat tggcaaaatc gttgaaaagc gcatagagtg tacggtgtat 120 tccgtcgata acaacggtaa tatctacacc cagccggtag ctcagtggca cgaccgaggc 180 gaacaggaag tgttcgagta ttgcttggaa gatggctccc ttatccgcgc cactaaagac 240 cataagttta tgacggttga cgggcagatg ctgcctatag acgaaatatt tgagagagag 300 ctggacttga tgagagtcga taatctgcca aat 333 <210> SEQ ID NO 424 <211> LENGTH: 180 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 424 ggcggatctg gcggtagtgg gggttccgga tccataaaga tagctactag gaaatatctt 60 ggcaaacaaa acgtctatga cataggagtt gagcgagatc acaattttgc tttgaagaat 120 gggttcatcg cgtctaattg cttcaacgct agcggcgggt caggaggctc tggtggaagc 180 <210> SEQ ID NO 425 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 425 aatcgagaag cgactcgaca 20 <210> SEQ ID NO 426 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 426 tgccctgcag gggagtgagc 20 <210> SEQ ID NO 427 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 427 gaagcgactc gacatggagg 20 <210> SEQ ID NO 428 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 428 cctgcagggg agtgagcagc 20

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 428 <210> SEQ ID NO 1 <211> LENGTH: 4 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 1 ttaa 4 <210> SEQ ID NO 2 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 2 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 3 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 3 atggcccagc acagcgacta cagcgacgac gagttctgtg ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 4 <211> LENGTH: 568 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 4 Met Ser Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp

195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Trp Ser Pro Tyr Thr Asp Ser Trp Tyr His 290 295 300 Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala Leu 305 310 315 320 Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg Gly 325 330 335 Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr Lys 340 345 350 Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys Lys 355 360 365 Pro Val Tyr Leu Ile Ser Ser His Ser Ala Glu Met Glu Glu Ser Gln 370 375 380 Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn Ala Leu 385 390 395 400 Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp Gln Tyr 405 410 415 Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Trp Lys Trp Thr Lys Arg Leu 420 425 430 Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr Ala Val Tyr 435 440 445 Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe Leu Lys Gln 450 455 460 Thr Ala His Trp Leu Thr Asp Asp Ile Pro Glu Asp Met Asp Ile Val 465 470 475 480 Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met Arg Ala Lys Pro 485 490 495 Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp Met Arg Lys His 500 505 510 Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys Asn Ile Leu Arg 515 520 525 Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser Glu Thr Arg Tyr 530 535 540 Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly Ala Cys Phe Glu 545 550 555 560 Lys Tyr His Thr Leu Lys Asn Tyr 565 <210> SEQ ID NO 5 <211> LENGTH: 1716 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 5 atgtcgcagc attcagacta ttctcatgat gagttttgtg cagacaagtt gtccaattat 60 tcttgtgata gcgatcttga aaatgcgagt acaagtgatg aagattctag tgatgatgaa 120 gtaatggtgc gtcccaggac attgaggcga cgaagaattt cgagctccag ctctgactca 180 gagtcagata tagaaggcgg gagagaagaa tggtcgcatg ttgataatcc accggtctta 240 gaagattttt tagggcatca aggattaaac acagatgctg ttataaataa tatagaagat 300 gccgtgaaat tatttatcgg agatgatttt tttgaatttc ttgtagagga gtcaaacagg 360 tattataatc aaaataggaa taatttcaaa ctttcaaaaa aaagcctaaa gtggaaagat 420 ataacccctc aagagatgaa gaagttttta gggttaattg ttctcatggg acaggtgcgc 480 aaagatagaa gagatgacta ttggaccacg gagccatgga cggagacgcc atattttggt 540 aaaacgatga cgagagacag gttccgacag atatggaaag cttggcactt caataataat 600 gcggatatcg taaatgaatc agatagactt tgcaaagtga gaccagtact agattatttt 660 gtgcctaaat ttataaatat ttacaaacct catcagcaat tatcactaga tgaagggatc 720 gtaccttgga ggggaagatt attctttagg gtatataatg ctggcaagat cgttaaatat 780 ggaatattgg ttcgtttgtt gtgcgaaagt gatacaggat atatctgtaa catggaaatt 840 tattgcggcg aaggaaagcg attattggaa acgatacaaa cagtagtgtc tccatacact 900 gattcgtggt accatatata tatggacaat tattataata gcgtcgcaaa ttgtgaagca 960 cttatgaaaa acaaattcag aatatgtgga acaatccgga aaaatcgagg tatacctaaa 1020 gattttcaaa caatttcttt gaaaaaaggt gaaacaaaat ttataaggaa aaatgatata 1080 ttgttacaag tgtggcaatc aaaaaagcct gtatacctga tttcttcgat tcattctgcg 1140 gagatggaag aaagtcagaa tattgacaga acatcaaaaa agaaaattgt caaaccgaat 1200 gcactcattg actacaataa acatatgaaa ggtgttgacc gggccgacca atacctttca 1260 tattattcga tattgcggag gacggtcaaa tggacaaaaa ggttggcaat gtatatgata 1320 aattgcgcat tatttaattc ttatgcagtt tacaaatcag tgaggcaaag aaaaatgggt 1380 tttaaaatgt ttttgaaaca aacagctatc cactggttga cggatgatat tccagaggac 1440 atggacattg ttccagacct tcaaccagta ccgtctactt ctggaatgcg ggctaaacca 1500 cctacatctg atccaccatg caggctatcg atggacatga gaaagcatac gttacaggca 1560 attgtcggaa gtggaaaaaa gaaaaacatt ttgagaaggt gtcgcgtatg ttccgttcat 1620 aaattgcgca gtgagacacg ctacatgtgc aaattttgca atatacctct acataaaggg 1680 gcgtgttttg aaaaatatca tacgctaaaa aactat 1716 <210> SEQ ID NO 6 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 6 atggcccagc acagcgacta cagcgacgac gagttctgtg ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaagagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 7 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 7 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Lys Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp

180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 8 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 8 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 9 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 9 Met Ala Gln His Ser Asp Tyr Pro Asp Asp Glu Phe Arg Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525

Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 10 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 10 Met Gly Ser Ser Leu Asp Asp Glu His Ile Leu Ser Ala Leu Leu Gln 1 5 10 15 Ser Asp Asp Glu Leu Val Gly Glu Asp Ser Asp Ser Glu Ile Ser Asp 20 25 30 His Val Ser Glu Asp Asp Val Gln Ser Asp Thr Glu Glu Ala Phe Ile 35 40 45 Asp Glu Val His Glu Val Gln Pro Thr Ser Ser Gly Ser Glu Ile Leu 50 55 60 Asp Glu Gln Asn Val Ile Glu Gln Pro Gly Ser Ser Leu Ala Ser Asn 65 70 75 80 Lys Ile Leu Thr Leu Pro Gln Arg Thr Ile Arg Gly Lys Asn Lys His 85 90 95 Cys Trp Ser Thr Ser Lys Ser Thr Arg Arg Ser Arg Val Ser Ala Leu 100 105 110 Asn Ile Val Arg Ser Gln Arg Gly Pro Thr Arg Met Cys Arg Asn Ile 115 120 125 Tyr Asp Pro Leu Leu Cys Phe Lys Leu Phe Phe Thr Asp Glu Ile Ile 130 135 140 Ser Glu Ile Val Lys Trp Thr Asn Ala Glu Ile Ser Leu Lys Arg Arg 145 150 155 160 Glu Ser Met Thr Gly Ala Thr Phe Arg Asp Thr Asn Glu Asp Glu Ile 165 170 175 Tyr Ala Phe Phe Gly Ile Leu Val Met Thr Ala Val Arg Lys Asp Asn 180 185 190 His Met Ser Thr Asp Asp Leu Phe Asp Arg Ser Leu Ser Met Val Tyr 195 200 205 Val Ser Val Met Ser Arg Asp Arg Phe Asp Phe Leu Ile Arg Cys Leu 210 215 220 Arg Met Asp Asp Lys Ser Ile Arg Pro Thr Leu Arg Glu Asn Asp Val 225 230 235 240 Phe Thr Pro Val Arg Lys Ile Trp Asp Leu Phe Ile His Gln Cys Ile 245 250 255 Gln Asn Tyr Thr Pro Gly Ala His Leu Thr Ile Asp Glu Gln Leu Leu 260 265 270 Gly Phe Arg Gly Arg Cys Pro Phe Arg Met Tyr Ile Pro Asn Lys Pro 275 280 285 Ser Lys Tyr Gly Ile Lys Ile Leu Met Met Cys Asp Ser Gly Thr Lys 290 295 300 Tyr Met Ile Asn Gly Met Pro Tyr Leu Gly Arg Gly Thr Gln Thr Asn 305 310 315 320 Gly Val Pro Leu Gly Glu Tyr Tyr Val Lys Glu Leu Ser Lys Pro Val 325 330 335 Arg Gly Ser Cys Arg Asn Ile Thr Cys Asp Asn Trp Phe Thr Ser Ile 340 345 350 Pro Leu Ala Lys Asn Leu Leu Gln Glu Pro Tyr Lys Leu Thr Ile Val 355 360 365 Gly Thr Val Arg Ser Asn Lys Arg Glu Ile Pro Glu Val Leu Lys Asn 370 375 380 Ser Arg Ser Arg Pro Val Gly Thr Ser Met Phe Cys Phe Asp Gly Pro 385 390 395 400 Leu Thr Leu Val Ser Tyr Lys Pro Lys Pro Ala Lys Met Val Tyr Leu 405 410 415 Leu Ser Ser Cys Asp Glu Asp Ala Ser Ile Asn Glu Ser Thr Gly Lys 420 425 430 Pro Gln Met Val Met Tyr Tyr Asn Gln Thr Lys Gly Gly Val Asp Thr 435 440 445 Leu Asp Gln Met Cys Ser Val Met Thr Cys Ser Arg Lys Thr Asn Arg 450 455 460 Trp Pro Met Ala Leu Leu Tyr Gly Met Ile Asn Ile Ala Cys Ile Asn 465 470 475 480 Ser Phe Ile Ile Tyr Ser His Asn Val Ser Ser Lys Gly Glu Lys Val 485 490 495 Gln Ser Arg Lys Lys Phe Met Arg Asn Leu Tyr Met Ser Leu Thr Ser 500 505 510 Ser Phe Met Arg Lys Arg Leu Glu Ala Pro Thr Leu Lys Arg Tyr Leu 515 520 525 Arg Asp Asn Ile Ser Asn Ile Leu Pro Asn Glu Val Pro Gly Thr Ser 530 535 540 Asp Asp Ser Thr Glu Glu Pro Val Thr Lys Lys Arg Thr Tyr Cys Thr 545 550 555 560 Tyr Cys Pro Ser Lys Ile Arg Arg Lys Ala Asn Ala Ser Cys Lys Lys 565 570 575 Cys Lys Lys Val Ile Cys Arg Glu His Asn Ile Asp Met Cys Gln Ser 580 585 590 Cys Phe <210> SEQ ID NO 11 <211> LENGTH: 280 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 11 Met Ser Asn Pro Arg Lys Arg Ser Ile Pro Thr Cys Asp Val Asn Phe 1 5 10 15 Val Leu Glu Gln Leu Leu Ala Glu Asp Ser Phe Asp Glu Ser Asp Phe 20 25 30 Ser Glu Ile Asp Asp Ser Asp Asp Phe Ser Asp Ser Ala Ser Glu Asp 35 40 45 Tyr Thr Val Arg Pro Pro Ser Asp Ser Glu Ser Asp Gly Asn Ser Pro 50 55 60 Thr Ser Ala Asp Ser Gly Arg Ala Leu Lys Trp Ser Thr Arg Val Met 65 70 75 80 Ile Pro Arg Gln Arg Tyr Asp Phe Thr Gly Thr Pro Gly Arg Lys Val 85 90 95 Asp Val Ser Asp Thr Thr Asp Pro Leu Gln Tyr Phe Glu Leu Phe Phe 100 105 110 Thr Glu Glu Leu Val Ser Lys Ile Thr Ser Glu Met Asn Ala Gln Ala 115 120 125 Ala Leu Leu Ala Ser Lys Pro Pro Gly Pro Lys Gly Phe Ser Arg Met 130 135 140 Asp Lys Trp Lys Asp Thr Asp Asn Asp Glu Leu Lys Val Phe Phe Ala 145 150 155 160 Val Met Leu Leu Gln Gly Ile Val Gln Lys Pro Glu Leu Glu Met Phe 165 170 175 Trp Ser Thr Arg Pro Leu Leu Asp Ile Pro Tyr Leu Arg Gln Ile Met 180 185 190 Thr Gly Glu Arg Phe Leu Leu Leu Leu Arg Cys Leu His Phe Val Asn 195 200 205 Asn Ser Ser Ile Ser Ala Gly Gln Ser Lys Ala Gln Ile Ser Leu Gln 210 215 220 Lys Ile Lys Pro Val Phe Asp Phe Leu Val Asn Lys Phe Ser Thr Val 225 230 235 240 Tyr Thr Pro Asn Arg Asn Ile Ala Val Asp Glu Ser Leu Met Leu Phe 245 250 255 Lys Gly Arg Leu Ala Met Lys Gln Tyr Ile Pro Thr Lys Met Asn Leu 260 265 270 Lys Asp Ser Ala Asp Gly Leu Lys 275 280 <210> SEQ ID NO 12 <211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 12 Met Asp Leu Arg Cys Gln His Thr Val Leu Ser Ile Arg Glu Ser Arg 1 5 10 15 Gly Leu Leu Pro Asn Leu Lys Met Lys Thr Ser Arg Met Lys Lys Gly 20 25 30 Asp Ile Ile Phe Ser Arg Lys Gly Asp Ile Leu Leu Leu Ala Trp Lys 35 40 45 Asp Lys Arg Val Val Arg Met Ile Ser Ile His Asp Thr Ser Val Ser 50 55 60 Thr Thr Gly Lys Lys Asn Arg Lys Thr Gly Glu Asn Ile Val Lys Pro 65 70 75 80 Ala Cys Ile Lys Glu Tyr Asn Ala His Met Lys Gly Val Asp Arg Ala 85 90 95 Asp Gln Phe Leu Ser Cys Cys Ser Ile Leu Arg Lys Met Met Lys Trp 100 105 110 Thr Lys Lys Val Val Leu Tyr Leu Ile Asn Cys Gly Leu Phe Asn Ser 115 120 125 Phe Arg Val Tyr Asn Val Leu Asn Pro Gln Ala Lys Met Lys Tyr Lys 130 135 140 Gln Phe Leu Leu Ser Val Ala Arg Asp Trp Ile Met Asp Asp Asn Asn 145 150 155 160 Glu Gly Ser Pro Glu Pro Glu Thr Asn Leu Ser Ser Pro Ser Pro Gly 165 170 175 Gly Ala Arg Arg Ala Pro Arg Lys Asp Pro Pro Lys Arg Leu Ser Gly 180 185 190 Asp Met Lys Gln His Glu Pro Thr Cys Ile Pro Ala Ser Gly Lys Lys 195 200 205 Lys Phe Pro Thr Arg Ala Cys Arg Val Cys Ala His Gly Lys Arg Ser 210 215 220 Glu Ser Arg Tyr Leu Cys Lys Phe Cys Leu Val Pro Leu His Arg Gly 225 230 235 240

Lys Cys Phe Thr Gln Tyr His Thr Leu Lys Lys Tyr 245 250 <210> SEQ ID NO 13 <211> LENGTH: 432 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 13 Met Lys Ala Phe Leu Gly Val Ile Leu Asn Met Gly Val Leu Asn His 1 5 10 15 Pro Asn Leu Gln Ser Tyr Trp Ser Met Asp Phe Glu Ser His Ile Pro 20 25 30 Phe Phe Arg Ser Val Phe Lys Arg Glu Arg Phe Leu Gln Ile Phe Trp 35 40 45 Met Leu His Leu Lys Asn Asp Gln Lys Ser Ser Lys Asp Leu Arg Thr 50 55 60 Arg Thr Glu Lys Val Asn Cys Phe Leu Ser Tyr Leu Glu Met Lys Phe 65 70 75 80 Arg Glu Arg Phe Cys Pro Gly Arg Glu Ile Ala Val Asp Glu Ala Val 85 90 95 Val Gly Phe Lys Gly Lys Ile His Phe Ile Thr Tyr Asn Pro Lys Lys 100 105 110 Pro Thr Lys Trp Gly Ile Arg Leu Tyr Val Leu Ser Asp Ser Lys Cys 115 120 125 Gly Tyr Val His Ser Phe Val Pro Tyr Tyr Gly Gly Ile Thr Ser Glu 130 135 140 Thr Leu Val Arg Pro Asp Leu Pro Phe Thr Ser Arg Ile Val Leu Glu 145 150 155 160 Leu His Glu Arg Leu Lys Asn Ser Val Pro Gly Ser Gln Gly Tyr His 165 170 175 Phe Phe Thr Asp Arg Tyr Tyr Thr Ser Val Thr Leu Ala Lys Glu Leu 180 185 190 Phe Lys Glu Lys Thr His Leu Thr Gly Thr Ile Met Pro Asn Arg Lys 195 200 205 Asp Asn Pro Pro Val Ile Lys His Gln Lys Leu Lys Lys Gly Glu Ile 210 215 220 Val Ala Phe Arg Asp Glu Asn Val Met Leu Leu Ala Trp Lys Asp Lys 225 230 235 240 Arg Ile Val Thr Leu Ser Thr Trp Asp Ser Glu Thr Glu Ser Val Glu 245 250 255 Arg Arg Val Gly Gly Gly Lys Glu Ile Val Leu Lys Pro Lys Val Val 260 265 270 Thr Asn Tyr Thr Lys Phe Met Gly Gly Val Asp Ile Ala Asp Tyr Thr 275 280 285 Ser Thr Tyr Cys Phe Met Arg Lys Thr Leu Lys Trp Trp Arg Thr Leu 290 295 300 Phe Phe Trp Gly Leu Glu Val Ser Val Val Asn Ser Tyr Ile Leu Tyr 305 310 315 320 Lys Glu Cys Gln Lys Arg Lys Asn Glu Lys Pro Ile Thr His Val Lys 325 330 335 Phe Ile Arg Lys Leu Val His Asp Leu Val Gly Glu Phe Arg Asp Gly 340 345 350 Thr Leu Thr Ser Arg Gly Arg Leu Leu Ser Thr Asn Leu Glu Gln Arg 355 360 365 Leu Asp Gly Lys Leu His Ile Ile Thr Pro His Pro Asn Lys Lys His 370 375 380 Lys Asp Cys Val Val Cys Ser Asn Arg Lys Ile Lys Gly Gly Arg Arg 385 390 395 400 Glu Thr Ile Tyr Ile Cys Glu Thr Cys Glu Cys Lys Pro Gly Leu His 405 410 415 Val Gly Glu Cys Phe Lys Lys Tyr His Thr Met Lys Asn Tyr Arg Asp 420 425 430 <210> SEQ ID NO 14 <211> LENGTH: 662 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 14 Met Pro Ser Leu Arg Lys Arg Lys Glu Thr Asn Glu Thr Asp Thr Leu 1 5 10 15 Pro Glu Val Phe Asn Asp Asn Leu Ser Asp Ile Pro Ser Glu Ile Glu 20 25 30 Asp Ala Asp Asp Cys Phe Asp Asp Ser Gly Asp Asp Ser Thr Asp Ser 35 40 45 Thr Asp Ser Glu Ile Ile Arg Pro Val Arg Lys Arg Lys Val Ala Val 50 55 60 Leu Ser Ser Asp Ser Asp Thr Asp Glu Ala Thr Asp Asn Cys Trp Ser 65 70 75 80 Glu Ile Asp Thr Pro Pro Arg Leu Gln Met Phe Glu Gly His Ala Gly 85 90 95 Val Thr Thr Phe Pro Ser Gln Cys Asp Ser Val Pro Ser Val Thr Asn 100 105 110 Leu Phe Phe Gly Asp Glu Leu Phe Glu Met Leu Cys Lys Glu Leu Ser 115 120 125 Asn Tyr His Asp Gln Thr Ala Met Lys Arg Lys Thr Pro Ser Arg Thr 130 135 140 Leu Lys Trp Ser Pro Val Thr Gln Lys Asp Ile Lys Lys Phe Leu Gly 145 150 155 160 Leu Ile Ile Leu Met Gly Gln Thr Arg Lys Asp Ser Leu Lys Asp Tyr 165 170 175 Trp Ser Thr Asp Pro Leu Ile Cys Thr Pro Ile Phe Pro Gln Thr Met 180 185 190 Ser Arg His Arg Phe Glu Gln Ile Trp Thr Phe Trp His Phe Asn Asp 195 200 205 Asn Ala Lys Met Asp Ser Arg Ser Gly Arg Leu Phe Lys Ile Gln Pro 210 215 220 Val Leu Asp Tyr Phe Leu His Lys Phe Arg Thr Ile Tyr Lys Pro Lys 225 230 235 240 Gln Gln Leu Ser Leu Asp Glu Gly Met Ile Pro Trp Arg Gly Arg Phe 245 250 255 Lys Phe Arg Thr Tyr Asn Pro Ala Lys Ile Thr Lys Tyr Gly Leu Leu 260 265 270 Val Arg Met Val Cys Glu Ser Asp Thr Gly Tyr Ile Cys Ser Met Glu 275 280 285 Ile Tyr Thr Ala Glu Gly Arg Lys Leu Gln Glu Thr Val Leu Ser Val 290 295 300 Leu Gly Pro Tyr Leu Gly Ile Trp His His Ile Tyr Gln Asp Asn Tyr 305 310 315 320 Tyr Asn Ala Thr Ser Thr Ala Glu Leu Leu Leu Gln Asn Lys Thr Arg 325 330 335 Val Cys Gly Thr Ile Arg Glu Ser Arg Gly Leu Pro Pro Asn Leu Glu 340 345 350 Met Lys Thr Ser Arg Met Lys Lys Gly Asp Ile Ile Phe Ser Arg Lys 355 360 365 Gly Asp Ile Leu Leu Leu Ala Trp Lys Asp Lys Arg Val Val Arg Met 370 375 380 Ile Ser Thr Ile His Asp Thr Ser Val Ser Thr Thr Gly Lys Lys Asn 385 390 395 400 Arg Lys Thr Gly Glu Asn Ile Val Lys Pro Thr Cys Ile Lys Glu Tyr 405 410 415 Asn Ala His Met Lys Gly Val Asp Arg Ala Asp Gln Phe Leu Ser Cys 420 425 430 Cys Ser Ile Leu Arg Lys Thr Met Lys Trp Thr Lys Lys Val Val Leu 435 440 445 Tyr Leu Ile Asn Cys Gly Leu Phe Asn Ser Phe Arg Val Tyr Asn Val 450 455 460 Leu Asn Pro Gln Ala Lys Met Lys Tyr Lys Gln Phe Leu Leu Ser Val 465 470 475 480 Ala Arg Asp Trp Ile Thr Asp Asp Asn Asn Glu Gly Ser Pro Glu Pro 485 490 495 Glu Thr Asn Leu Ser Ser Pro Ser Pro Gly Gly Ala Arg Arg Ala Pro 500 505 510 Arg Lys Asp Pro Pro Lys Arg Leu Ser Gly Asp Met Lys Gln His Glu 515 520 525 Pro Thr Cys Ile Pro Ala Ser Gly Lys Lys Lys Phe Pro Thr Arg Ala 530 535 540 Cys Arg Val Cys Ala Ala His Gly Lys Arg Ser Glu Ser Arg Tyr Leu 545 550 555 560 Cys Lys Phe Cys Leu Val Pro Leu His Arg Gly Lys Cys Phe Thr Gln 565 570 575 Tyr His Thr Leu Lys Lys Tyr Met Asp Leu Arg Cys Gln His Thr Val 580 585 590 Leu Ser Thr Val Gly Arg Gly Tyr Ser Val Leu Ala Arg Phe Lys Pro 595 600 605 Arg Thr Asn Glu Arg Thr Gly Ser Ser His Cys His Val Gln Val Pro 610 615 620 Ala Gly Gly Gln Gly Pro Pro Ser Thr Ile Ile Ala Asn Gly Cys Gly 625 630 635 640 Cys Lys Leu Glu Pro Met Val Arg Thr Arg Ser Pro Thr Cys Leu Val 645 650 655 Ile Glu Phe Gly Cys Met 660 <210> SEQ ID NO 15 <211> LENGTH: 673 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 15 Met Pro Ser Leu Arg Lys Arg Lys Glu Thr Asn Glu Thr Asp Thr Leu 1 5 10 15 Pro Glu Val Phe Asn Asp Asn Leu Ser Asp Ile Pro Ser Glu Ile Glu 20 25 30 Asp Ala Asp Asp Cys Phe Asp Asp Ser Gly Asp Asp Ser Thr Asp Ser 35 40 45 Thr Glu Ser Glu Ile Ile Arg Pro Val Arg Lys Arg Lys Val Ala Val 50 55 60

Leu Ser Ser Asp Ser Asn Thr Asp Glu Ala Thr Asp Asn Cys Trp Ser 65 70 75 80 Glu Ile Asp Thr Pro Pro Arg Leu Gln Met Phe Glu Gly His Ala Gly 85 90 95 Val Thr Thr Phe Pro Ser Gln Cys Asp Ser Val Pro Ser Val Thr Asn 100 105 110 Leu Phe Phe Gly Asp Glu Leu Phe Glu Met Leu Cys Lys Glu Leu Ser 115 120 125 Asn Tyr His Asp Gln Thr Ala Met Lys Arg Lys Thr Pro Ser Arg Thr 130 135 140 Leu Lys Trp Ser Pro Val Thr Gln Lys Asp Ile Lys Lys Phe Leu Gly 145 150 155 160 Leu Ile Ile Leu Met Gly Gln Thr Arg Lys Asp Ser Trp Lys Asp Tyr 165 170 175 Trp Ser Thr Asp Pro Leu Ile Cys Thr Pro Ile Phe Pro Gln Thr Met 180 185 190 Ser Arg His Arg Phe Glu Gln Ile Trp Thr Phe Trp His Phe Asn Asp 195 200 205 Asn Ala Lys Met Asp Ser Cys Ser Gly Arg Leu Phe Lys Ile Gln Pro 210 215 220 Val Leu Asp Tyr Phe Leu His Lys Phe Arg Thr Ile Tyr Lys Pro Lys 225 230 235 240 Gln Gln Leu Ser Leu Asp Glu Gly Met Ile Pro Trp Arg Gly Arg Leu 245 250 255 Lys Phe Thr Tyr Asn Pro Ala Ile Thr Lys Tyr Gly Leu Leu Val Arg 260 265 270 Met Val Cys Glu Ser Asp Thr Gly Tyr Ile Cys Asn Met Glu Ile Tyr 275 280 285 Thr Ala Glu Arg Lys Lys Leu Gln Glu Thr Val Leu Ser Val Leu Gly 290 295 300 Pro Tyr Leu Gly Ile Trp His His Ile Tyr Gln Asp Asn Tyr Tyr Asn 305 310 315 320 Ala Thr Ser Thr Ala Glu Leu Leu Leu Gln Asn Lys Thr Arg Val Cys 325 330 335 Gly Thr Ile Arg Glu Ser Arg Gly Leu Pro Pro Asn Leu Lys Met Lys 340 345 350 Thr Ser Arg Met Lys Lys Gly Asp Ile Ile Phe Ser Arg Lys Gly Asp 355 360 365 Ile Leu Leu Leu Ala Trp Lys Asp Lys Arg Val Val Arg Met Ile Ser 370 375 380 Thr Ile His Asp Thr Ser Val Ser Thr Thr Gly Lys Lys Asn Arg Lys 385 390 395 400 Thr Gly Glu Asn Ile Val Lys Pro Thr Cys Ile Lys Glu Tyr Asn Ala 405 410 415 His Met Lys Gly Val Asp Arg Ala Asp Gln Phe Leu Ser Cys Cys Ser 420 425 430 Ile Leu Arg Lys Thr Thr Lys Trp Thr Lys Lys Val Val Leu Tyr Leu 435 440 445 Ile Asn Cys Gly Leu Phe Asn Ser Phe Arg Val Tyr Asn Ile Leu Asn 450 455 460 Pro Gln Ala Lys Met Lys Tyr Lys Gln Phe Leu Leu Ser Val Ala Arg 465 470 475 480 Asp Trp Ile Thr Asp Asp Asn Asn Glu Gly Ser Pro Glu Pro Glu Thr 485 490 495 Asn Leu Ser Ser Pro Ser Ser Gly Gly Ala Arg Arg Ala Pro Arg Lys 500 505 510 Asp Gln Pro Lys Arg Leu Ser Gly Asp Met Lys Gln His Glu Pro Thr 515 520 525 Cys Ile Pro Ala Ser Gly Lys Lys Lys Phe Pro Thr Ala Cys Arg Val 530 535 540 Cys Ala Ala His Gly Lys Arg Ser Glu Ser Arg Tyr Leu Arg Lys Phe 545 550 555 560 Cys Phe Val Pro Leu Arg Gly Lys Cys Phe Met Tyr His Thr Leu Lys 565 570 575 Lys Tyr Ser Glu Leu Phe Ser Leu Ile Val Val Ser Lys Ile Gln Asn 580 585 590 Val Ile Ile Tyr Lys Thr Thr Lys Val Tyr Met Arg Tyr Val Met Arg 595 600 605 Ser His Cys Pro Leu Ser Phe Leu Val Phe Ala Pro Ser Val Lys Asp 610 615 620 Arg Ser Arg Val Phe Ser Phe Phe Thr Arg His Leu Leu Trp Thr Leu 625 630 635 640 Asp Val Asn Thr Leu Ser Cys Pro His Arg Met Lys Arg Ser His Trp 645 650 655 Trp Lys Pro Cys Arg Ser Ile Tyr Glu Lys Leu Tyr Asn Cys Thr Asn 660 665 670 Pro <210> SEQ ID NO 16 <211> LENGTH: 254 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 16 Met Asp Leu Arg Cys Gln His Thr Val Leu Ser Ile Arg Glu Ser Arg 1 5 10 15 Gly Leu Pro Pro Asn Leu Lys Met Lys Thr Ser Arg Met Lys Lys Gly 20 25 30 Asp Ile Ile Phe Ser Arg Lys Gly Asp Ile Leu Leu Leu Ala Trp Lys 35 40 45 Asp Lys Arg Val Val Arg Met Ile Ser Thr Ile His Asp Thr Ser Val 50 55 60 Ser Thr Thr Gly Lys Lys Asn Arg Lys Thr Gly Glu Asn Ile Val Lys 65 70 75 80 Pro Ala Cys Ile Lys Glu Tyr Asn Ala His Met Lys Gly Val Asp Arg 85 90 95 Ala Asp Gln Phe Leu Ser Cys Cys Ser Ile Leu Arg Lys Thr Met Lys 100 105 110 Trp Thr Lys Lys Val Val Leu Tyr Leu Ile Asn Cys Gly Leu Phe Asn 115 120 125 Ser Phe Arg Val Tyr Asn Val Leu Asn Pro Gln Ala Lys Met Lys Tyr 130 135 140 Lys Gln Phe Leu Leu Ser Val Ala Arg Asp Trp Ile Thr Asp Asp Asn 145 150 155 160 Asn Glu Gly Ser Pro Glu Pro Glu Thr Asn Leu Ser Ser Pro Ser Pro 165 170 175 Gly Gly Ala Arg Arg Ala Pro Arg Lys Asp Pro Pro Lys Arg Leu Ser 180 185 190 Gly Asp Met Lys Gln His Glu Pro Thr Cys Ile Pro Ala Ser Gly Lys 195 200 205 Lys Lys Phe Pro Thr Arg Ala Cys Arg Val Cys Ala Ala His Gly Lys 210 215 220 Arg Ser Glu Ser Arg Tyr Leu Cys Lys Phe Cys Leu Val Pro Leu His 225 230 235 240 Arg Gly Lys Cys Phe Thr Gln Tyr His Thr Leu Lys Lys Tyr 245 250 <210> SEQ ID NO 17 <211> LENGTH: 594 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 17 Met Gly Ser Ser Leu Asp Asp Glu His Ile Leu Ser Ala Leu Leu Gln 1 5 10 15 Ser Asp Asp Glu Leu Val Gly Glu Asp Ser Asp Ser Glu Val Ser Asp 20 25 30 His Val Ser Glu Asp Asp Val Gln Ser Asp Thr Glu Glu Ala Phe Ile 35 40 45 Asp Glu Val His Glu Val Gln Pro Thr Ser Ser Gly Ser Glu Ile Leu 50 55 60 Asp Glu Gln Asn Val Ile Glu Gln Pro Gly Ser Ser Leu Ala Ser Asn 65 70 75 80 Arg Ile Leu Thr Leu Pro Gln Arg Thr Ile Arg Gly Lys Asn Lys His 85 90 95 Cys Trp Ser Thr Ser Lys Pro Thr Arg Arg Ser Arg Val Ser Ala Leu 100 105 110 Asn Ile Val Arg Ser Gln Arg Gly Pro Thr Arg Met Cys Arg Asn Ile 115 120 125 Tyr Asp Pro Leu Leu Cys Phe Lys Leu Phe Phe Thr Asp Glu Ile Ile 130 135 140 Ser Glu Ile Val Lys Trp Thr Asn Ala Glu Ile Ser Leu Lys Arg Arg 145 150 155 160 Glu Ser Met Thr Ser Ala Thr Phe Arg Asp Thr Asn Glu Asp Glu Ile 165 170 175 Tyr Ala Phe Phe Gly Ile Leu Val Met Thr Ala Val Arg Lys Asp Asn 180 185 190 His Met Ser Thr Asp Asp Leu Phe Asp Arg Ser Leu Ser Met Val Tyr 195 200 205 Val Ser Val Met Ser Arg Asp Arg Phe Asp Phe Leu Ile Arg Cys Leu 210 215 220 Arg Met Asp Asp Lys Ser Ile Arg Pro Thr Leu Arg Glu Asn Asp Val 225 230 235 240 Phe Thr Pro Val Arg Lys Ile Trp Asp Leu Phe Ile His Gln Cys Ile 245 250 255 Gln Asn Tyr Thr Pro Gly Ala His Leu Thr Ile Asp Glu Gln Leu Leu 260 265 270 Gly Phe Arg Gly Arg Cys Pro Phe Arg Val Tyr Ile Pro Asn Lys Pro 275 280 285 Ser Lys Tyr Gly Ile Lys Ile Leu Met Met Cys Asp Ser Gly Thr Lys 290 295 300 Tyr Met Ile Asn Gly Met Pro Tyr Leu Gly Arg Gly Thr Gln Thr Asn 305 310 315 320 Gly Val Pro Leu Gly Glu Tyr Tyr Val Lys Glu Leu Ser Lys Pro Val 325 330 335 His Gly Ser Cys Arg Asn Ile Thr Cys Asp Asn Trp Phe Thr Ser Ile 340 345 350

Pro Leu Ala Lys Asn Leu Leu Gln Glu Pro Tyr Lys Leu Thr Ile Val 355 360 365 Gly Thr Val Arg Ser Asn Lys Arg Glu Ile Pro Glu Val Leu Lys Asn 370 375 380 Ser Arg Ser Arg Pro Val Gly Thr Ser Met Phe Cys Phe Asp Gly Pro 385 390 395 400 Leu Thr Leu Val Ser Tyr Lys Pro Lys Pro Ala Lys Met Val Tyr Leu 405 410 415 Leu Ser Ser Cys Asp Glu Asp Ala Ser Ile Asn Glu Ser Thr Gly Lys 420 425 430 Pro Gln Met Val Met Tyr Tyr Asn Gln Thr Lys Gly Gly Val Asp Thr 435 440 445 Leu Asp Gln Met Cys Ser Val Met Thr Cys Ser Arg Lys Thr Asn Arg 450 455 460 Trp Pro Met Ala Leu Leu Tyr Gly Met Ile Asn Ile Ala Cys Ile Asn 465 470 475 480 Ser Phe Ile Ile Tyr Ser His Asn Val Ser Ser Lys Gly Glu Lys Val 485 490 495 Gln Ser Arg Lys Lys Phe Met Arg Asn Leu Tyr Met Gly Leu Thr Ser 500 505 510 Ser Phe Met Arg Lys Arg Leu Glu Ala Pro Thr Leu Lys Arg Tyr Leu 515 520 525 Arg Asp Asn Ile Ser Asn Ile Leu Pro Lys Glu Val Pro Gly Thr Ser 530 535 540 Asp Asp Ser Thr Glu Glu Pro Val Met Lys Lys Arg Thr Tyr Cys Thr 545 550 555 560 Tyr Cys Pro Ser Lys Ile Arg Arg Lys Ala Ser Ala Ser Cys Lys Lys 565 570 575 Cys Lys Lys Val Ile Cys Arg Glu His Asn Ile Asp Met Cys Gln Ser 580 585 590 Cys Phe <210> SEQ ID NO 18 <211> LENGTH: 1782 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 18 atgggcagca gcctggacga cgagcacatc ctgagcgccc tgctgcagag cgacgacgag 60 ctggtcggcg aggacagcga cagcgaggtg agcgaccacg tgagcgagga cgacgtgcag 120 tccgacaccg aggaggcctt catcgacgag gtgcacgagg tgcagcctac cagcagcggc 180 tccgagatcc tggacgagca gaacgtgatc gagcagcccg gcagctccct ggccagcaac 240 aggatcctga ccctgcccca gaggaccatc aggggcaaga acaagcactg ctggtccacc 300 tccaagccca ccaggcggag cagggtgtcc gccctgaaca tcgtgagaag ccagaggggc 360 cccaccagga tgtgcaggaa catctacgac cccctgctgt gcttcaagct gttcttcacc 420 gacgagatca tcagcgagat cgtgaagtgg accaacgccg agatcagcct gaagaggcgg 480 gagagcatga cctccgccac cttcagggac accaacgagg acgagatcta cgccttcttc 540 ggcatcctgg tgatgaccgc cgtgaggaag gacaaccaca tgagcaccga cgacctgttc 600 gacagatccc tgagcatggt gtacgtgagc gtgatgagca gggacagatt cgacttcctg 660 atcagatgcc tgaggatgga cgacaagagc atcaggccca ccctgcggga gaacgacgtg 720 ttcacccccg tgagaaagat ctgggacctg ttcatccacc agtgcatcca gaactacacc 780 cctggcgccc acctgaccat cgacgagcag ctgctgggct tcaggggcag gtgccccttc 840 agggtctata tccccaacaa gcccagcaag tacggcatca agatcctgat gatgtgcgac 900 agcggcacca agtacatgat caacggcatg ccctacctgg gcaggggcac ccagaccaac 960 ggcgtgcccc tgggcgagta ctacgtgaag gagctgtcca agcccgtcca cggcagctgc 1020 agaaacatca cctgcgacaa ctggttcacc agcatccccc tggccaagaa cctgctgcag 1080 gagccctaca agctgaccat cgtgggcacc gtgagaagca acaagagaga gatccccgag 1140 gtcctgaaga acagcaggtc caggcccgtg ggcaccagca tgttctgctt cgacggcccc 1200 ctgaccctgg tgtcctacaa gcccaagccc gccaagatgg tgtacctgct gtccagctgc 1260 gacgaggacg ccagcatcaa cgagagcacc ggcaagcccc agatggtgat gtactacaac 1320 cagaccaagg gcggcgtgga caccctggac cagatgtgca gcgtgatgac ctgcagcaga 1380 aagaccaaca ggtggcccat ggccctgctg tacggcatga tcaacatcgc ctgcatcaac 1440 agcttcatca tctacagcca caacgtgagc agcaagggcg agaaggtgca gagccggaaa 1500 aagttcatgc ggaacctgta catgggcctg acctccagct tcatgaggaa gaggctggag 1560 gcccccaccc tgaagagata cctgagggac aacatcagca acatcctgcc caaagaggtg 1620 cccggcacca gcgacgacag caccgaggag cccgtgatga agaagaggac ctactgcacc 1680 tactgtccca gcaagatcag aagaaaggcc agcgccagct gcaagaagtg taagaaggtc 1740 atctgccggg agcacaacat cgacatgtgc cagagctgtt tc 1782 <210> SEQ ID NO 19 <211> LENGTH: 205 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 19 ttaaccctag aaagataatc atattgtgac gtacgttaaa gataatcatg cgtaaaattg 60 acgcatgtgt tttatcggtc tgtatatcga ggtttattta ttaatttgaa tagatattaa 120 gttttattat atttacactt acatactaat aataaattca acaaacaatt tatttatgtt 180 tatttattta ttaaaaaaaa acaaa 205 <210> SEQ ID NO 20 <211> LENGTH: 310 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 20 atctataaca agaaaatata tatataataa gttatcacgt aagtagaaca tgaaataaca 60 atataattat cgtatgagtt aaatcttaaa agtcacgtaa aagataatca tgcgtcattt 120 tgactcacgc ggtcgttata gttcaaaatc agtgacactt accgcattga caagcacgcc 180 tcacgggagc tccaagcggc gactgagatg tcctaaatgc acagcgacgg attcgcgcta 240 tttagaaaga gagagcaata tttcaagaat gcatgcgtca attttacgca gactatcttt 300 ctagggttaa 310 <210> SEQ ID NO 21 <211> LENGTH: 157 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 21 ttaacacttg gattgcggga aacgagttaa gtcggctcgc gtgaattgcg cgtactccgc 60 gggagccgtc ttaactcggt tcatatagat ttgcggtgga gtgcgggaaa cgtgtaaact 120 cgggccgatt gtaactgcgt attaccaaat atttgtt 157 <210> SEQ ID NO 22 <211> LENGTH: 212 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 22 aattatttat gtactgaata gataaaaaaa tgtctgtgat tgaataaatt ttcatttttt 60 acacaagaaa ccgaaaattt catttcaatc gaacccatac ttcaaaagat ataggcattt 120 taaactaact ctgattttgc gcgggaaacc taaataattg cccgcgccat cttatatttt 180 ggcgggaaat tcacccgaca ccgtagtgtt aa 212 <210> SEQ ID NO 23 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 23 tggccggcct gaccactgg 19 <210> SEQ ID NO 24 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 24 tgaaggcctg gccggcctg 19 <210> SEQ ID NO 25 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 25 tgagcactga aggcctggc 19 <210> SEQ ID NO 26 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 26 tccactgagc actgaaggc 19 <210> SEQ ID NO 27 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 27 tggtttccac tgagcactg 19

<210> SEQ ID NO 28 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 28 tggggaaaat gacccaaca 19 <210> SEQ ID NO 29 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 29 taggacagtg gggaaaatg 19 <210> SEQ ID NO 30 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 30 tccagggaca cggtgctag 19 <210> SEQ ID NO 31 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 31 tcagagccag gagtcctgg 19 <210> SEQ ID NO 32 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 32 tccttcagag ccaggagtc 19 <210> SEQ ID NO 33 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 33 tcctccttca gagccagga 19 <210> SEQ ID NO 34 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 34 tccagcccct cctccttca 19 <210> SEQ ID NO 35 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 35 tccgagcttg acccttgga 19 <210> SEQ ID NO 36 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 36 tggtttccga gcttgaccc 19 <210> SEQ ID NO 37 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 37 tggggtggtt tccgagcttt ggggtggttt ccgagctt 38 <210> SEQ ID NO 38 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 38 tctgctgggg tggtttccg 19 <210> SEQ ID NO 39 <211> LENGTH: 38 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 39 tgcagagtat ctgctggggt gcagagtatc tgctgggg 38 <210> SEQ ID NO 40 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 40 ccaatcccct cagt 14 <210> SEQ ID NO 41 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 41 cagtgctcag tggaa 15 <210> SEQ ID NO 42 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 42 gaaacatccg gcgactca 18 <210> SEQ ID NO 43 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 43 tcgcccctca aatcttaca 19 <210> SEQ ID NO 44 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 44 tcaaatctta cagctgctc 19 <210> SEQ ID NO 45 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 45 tcttacagct gctcactcc 19 <210> SEQ ID NO 46 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 46 tacagctgct cactcccct 19 <210> SEQ ID NO 47 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 47 tgctcactcc cctgcaggg 19 <210> SEQ ID NO 48 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 48 tcccctgcag ggcaacgcc 19

<210> SEQ ID NO 49 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 49 tgcagggcaa cgcccaggg 19 <210> SEQ ID NO 50 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 50 tctcgattat gggcgggat 19 <210> SEQ ID NO 51 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 51 tcgcttctcg attatgggc 19 <210> SEQ ID NO 52 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 52 tgtcgagtcg cttctcgat 19 <210> SEQ ID NO 53 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 53 tccatgtcga gtcgcttct 19 <210> SEQ ID NO 54 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 54 tcgcctccat gtcgagtcg 19 <210> SEQ ID NO 55 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 55 tcgtcatcgc ctccatgtc 19 <210> SEQ ID NO 56 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 56 tgatctcgtc atcgcctcc 19 <210> SEQ ID NO 57 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 57 gcttcagctt ccta 14 <210> SEQ ID NO 58 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 58 ctgtgatcat gcca 14 <210> SEQ ID NO 59 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 59 acagtggtac acacct 16 <210> SEQ ID NO 60 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 60 ccacccccca ctaag 15 <210> SEQ ID NO 61 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 61 cattggccgg gcac 14 <210> SEQ ID NO 62 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 62 gcttgaaccc aggaga 16 <210> SEQ ID NO 63 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 63 acacccgatc cactggg 17 <210> SEQ ID NO 64 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 64 gctgcatcaa cccc 14 <210> SEQ ID NO 65 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 65 gccacaaaca gaaata 16 <210> SEQ ID NO 66 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 66 ggtggctcat gcctg 15 <210> SEQ ID NO 67 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 67 gatttgcaca gctcat 16 <210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 68 aagctctgag gagca 15 <210> SEQ ID NO 69 <211> LENGTH: 13 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 69

ccctagctgt ccc 13 <210> SEQ ID NO 70 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 70 gcctagcatg ctag 14 <210> SEQ ID NO 71 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 71 atgggcttca cggat 15 <210> SEQ ID NO 72 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 72 gaaactatgc ctgc 14 <210> SEQ ID NO 73 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 73 gcaccattgc tccc 14 <210> SEQ ID NO 74 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 74 gacatgcaac tcag 14 <210> SEQ ID NO 75 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 75 acaccactag gggt 14 <210> SEQ ID NO 76 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 76 gtctgctaga cagg 14 <210> SEQ ID NO 77 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 77 ggcctagaca ggctg 15 <210> SEQ ID NO 78 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 78 gaggcattct tatcg 15 <210> SEQ ID NO 79 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 79 gcctggaaac gttcc 15 <210> SEQ ID NO 80 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 80 gtgctctgac aata 14 <210> SEQ ID NO 81 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 81 gttttgcagc ctcc 14 <210> SEQ ID NO 82 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 82 acagctgtgg aacgt 15 <210> SEQ ID NO 83 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 83 ggctctcttc ctcct 15 <210> SEQ ID NO 84 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 84 ctatcccaaa actct 15 <210> SEQ ID NO 85 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 85 gaaaaactat gtat 14 <210> SEQ ID NO 86 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 86 aggcaggctg gttga 15 <210> SEQ ID NO 87 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 87 caatacaacc acgc 14 <210> SEQ ID NO 88 <211> LENGTH: 15 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 88 atgacggact caact 15 <210> SEQ ID NO 89 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 89 cacaacattt gtaa 14 <210> SEQ ID NO 90 <211> LENGTH: 14 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 90

atttccagtg caca 14 <210> SEQ ID NO 91 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 91 gtttagctca cccgtgagcc 20 <210> SEQ ID NO 92 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 92 cccaatatta ttgttctctg 20 <210> SEQ ID NO 93 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 93 ggggtgggat aggggatacg 20 <210> SEQ ID NO 94 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 94 ggatccccct ctacatttaa 20 <210> SEQ ID NO 95 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 95 gtgatcttgt acaaatcatt 20 <210> SEQ ID NO 96 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 96 ctacacagaa tctgttagaa 20 <210> SEQ ID NO 97 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 97 taagctagag aatagatctc 20 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 98 tcaatacact taatgattta 20 <210> SEQ ID NO 99 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 99 caccgggagc cacgaaaaca gatcc 25 <210> SEQ ID NO 100 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 100 caccgcgaaa acagatccag ggaca 25 <210> SEQ ID NO 101 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 101 caccgagatc cagggacacg gtgct 25 <210> SEQ ID NO 102 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 102 caccggacac ggtgctagga cagtg 25 <210> SEQ ID NO 103 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 103 caccggaaaa tgacccaaca gcctc 25 <210> SEQ ID NO 104 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 104 caccggcctg gccggcctga ccact 25 <210> SEQ ID NO 105 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 105 caccgctgag cactgaaggc ctggc 25 <210> SEQ ID NO 106 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 106 caccgtggtt tccactgagc actga 25 <210> SEQ ID NO 107 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 107 caccggatag ccaggagtcc tttcg 25 <210> SEQ ID NO 108 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 108 caccggcgct tccagtgctc agact 25 <210> SEQ ID NO 109 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 109 caccgcagtg ctcagactag ggaag 25 <210> SEQ ID NO 110 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 110 caccggcccc tcctccttca gagcc 25 <210> SEQ ID NO 111 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence

<400> SEQUENCE: 111 caccgtcctt cagagccagg agtcc 25 <210> SEQ ID NO 112 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 112 caccgtggtt tccgagcttg accct 25 <210> SEQ ID NO 113 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 113 caccgctgca gagtatctgc tgggg 25 <210> SEQ ID NO 114 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 114 caccgcgttc ctgcagagta tctgc 25 <210> SEQ ID NO 115 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 115 aaacggatct gttttcgtgg ctccc 25 <210> SEQ ID NO 116 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 116 aaactgtccc tggatctgtt ttcgc 25 <210> SEQ ID NO 117 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 117 aaacagcacc gtgtccctgg atctc 25 <210> SEQ ID NO 118 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 118 aaaccactgt cctagcaccg tgtcc 25 <210> SEQ ID NO 119 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 119 aaacgaggct gttgggtcat tttcc 25 <210> SEQ ID NO 120 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 120 aaacagtggt caggccggcc aggcc 25 <210> SEQ ID NO 121 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 121 aaacgccagg ccttcagtgc tcagc 25 <210> SEQ ID NO 122 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 122 aaactcagtg ctcagtggaa accac 25 <210> SEQ ID NO 123 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 123 aaaccgaaag gactcctggc tatcc 25 <210> SEQ ID NO 124 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 124 aaacagtctg agcactggaa gcgcc 25 <210> SEQ ID NO 125 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 125 aaaccttccc tagtctgagc actgc 25 <210> SEQ ID NO 126 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 126 aaacggctct gaaggaggag gggcc 25 <210> SEQ ID NO 127 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 127 aaacggactc ctggctctga aggac 25 <210> SEQ ID NO 128 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 128 aaacagggtc aagctcggaa accac 25 <210> SEQ ID NO 129 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 129 aaacccccag cagatactct gcagc 25 <210> SEQ ID NO 130 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 130 aaacgcagat actctgcagg aacgc 25 <210> SEQ ID NO 131 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 131 tcccctccca gaaagacctg 20 <210> SEQ ID NO 132 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence

<400> SEQUENCE: 132 tgggctccaa gcaatcctgg 20 <210> SEQ ID NO 133 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 133 gtggctcagg aggtacctgg 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 134 gagccacgaa aacagatcca 20 <210> SEQ ID NO 135 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 135 aagtgaacgg ggaagggagg 20 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 136 gacaaaagcc gaagtccagg 20 <210> SEQ ID NO 137 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 137 gtggttgata aacccacgtg 20 <210> SEQ ID NO 138 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 138 tgggaacagc cacagcaggg 20 <210> SEQ ID NO 139 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 139 gcaggggaac ggggatgcag 20 <210> SEQ ID NO 140 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 140 gagatggtgg acgaggaagg 20 <210> SEQ ID NO 141 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 141 gagatggctc caggaaatgg 20 <210> SEQ ID NO 142 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 142 taaggaatct gcctaacagg 20 <210> SEQ ID NO 143 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 143 tcaggagact aggaaggagg 20 <210> SEQ ID NO 144 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 144 tataaggtgg tcccagctcg 20 <210> SEQ ID NO 145 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 145 ctggaagatg ccatgacagg 20 <210> SEQ ID NO 146 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 146 gcacagacta gagaggtaag 20 <210> SEQ ID NO 147 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 147 acagactaga gaggtaaggg 20 <210> SEQ ID NO 148 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 148 gagaggtgac ccgaatccac 20 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 149 gcacaggccc cagaaggaga 20 <210> SEQ ID NO 150 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 150 ccggagagga cccagacacg 20 <210> SEQ ID NO 151 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 151 gagaggaccc agacacgggg 20 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 152 gcaacacagc agagagcaag 20 <210> SEQ ID NO 153 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:

<223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 153 gaagagggag tggaggaaga 20 <210> SEQ ID NO 154 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 154 aagacggaac ctgaaggagg 20 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 155 agaaagcggc acaggcccag 20 <210> SEQ ID NO 156 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 156 gggaaacagt gggccagagg 20 <210> SEQ ID NO 157 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 157 gtccggactc aggagagaga 20 <210> SEQ ID NO 158 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 158 ggcacagcaa gggcactcgg 20 <210> SEQ ID NO 159 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 159 gaagagggga agtcgaggga 20 <210> SEQ ID NO 160 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 160 gggaatggta aggaggcctg 20 <210> SEQ ID NO 161 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 161 gcagagtggt cagcacagag 20 <210> SEQ ID NO 162 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 162 gcacagagtg gctaagccca 20 <210> SEQ ID NO 163 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 163 gacggggtgt cagcataggg 20 <210> SEQ ID NO 164 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 164 gcccagggcc aggaacgacg 20 <210> SEQ ID NO 165 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 165 ggtggagtcc agcacggcgc 20 <210> SEQ ID NO 166 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 166 acaggccgcc aggaactcgg 20 <210> SEQ ID NO 167 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 167 actaggaagt gtgtagcacc 20 <210> SEQ ID NO 168 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 168 atgaatagca gactgccccg 20 <210> SEQ ID NO 169 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 169 acacccctaa aagcacagtg 20 <210> SEQ ID NO 170 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 170 caaggagttc cagcaggtgg 20 <210> SEQ ID NO 171 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 171 aaggagttcc agcaggtggg 20 <210> SEQ ID NO 172 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 172 tggaaagagg agggaagagg 20 <210> SEQ ID NO 173 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 173 tcgaattcct aactgccccg 20 <210> SEQ ID NO 174 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence

<220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 174 gacctgccca gcacaccctg 20 <210> SEQ ID NO 175 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 175 ggagcagctg cggcagtggg 20 <210> SEQ ID NO 176 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 176 gggagggaga gcttggcagg 20 <210> SEQ ID NO 177 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 177 gttacgtggc caagaagcag 20 <210> SEQ ID NO 178 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 178 gctgaacaga gaagagctgg 20 <210> SEQ ID NO 179 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 179 tctgagggtg gagggactgg 20 <210> SEQ ID NO 180 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 180 ggagaggtga gggacttggg 20 <210> SEQ ID NO 181 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 181 gtgaaccagg cagacaacga 20 <210> SEQ ID NO 182 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 182 caggtacctc ctgagccacg 20 <210> SEQ ID NO 183 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 183 gggggagtag gggcatgcag 20 <210> SEQ ID NO 184 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 184 gcaaatggcc agcaagggtg 20 <210> SEQ ID NO 185 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 185 caccgaatcg agaagcgact cgaca 25 <210> SEQ ID NO 186 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 186 caccggtccc tgggcgttgc cctgc 25 <210> SEQ ID NO 187 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 187 caccgccctg ggcgttgccc tgcag 25 <210> SEQ ID NO 188 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 188 caccgccgtg ggaagataaa ctaat 25 <210> SEQ ID NO 189 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 189 caccgtcccc tgcagggcaa cgccc 25 <210> SEQ ID NO 190 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 190 caccggtcga gtcgcttctc gatta 25 <210> SEQ ID NO 191 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 191 caccgctgct gcctcccgtc ttgta 25 <210> SEQ ID NO 192 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 192 caccggagtg ccgcaatacc tttat 25 <210> SEQ ID NO 193 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 193 caccgacact ttggtggtgc agcaa 25 <210> SEQ ID NO 194 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 194 caccgtctca aatggtataa aactc 25 <210> SEQ ID NO 195 <211> LENGTH: 25 <212> TYPE: DNA

<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 195 caccgaatcc cgcccataat cgaga 25 <210> SEQ ID NO 196 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 196 caccgtcccg cccataatcg agaag 25 <210> SEQ ID NO 197 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 197 caccgcccat aatcgagaag cgact 25 <210> SEQ ID NO 198 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 198 caccggagaa gcgactcgac atgga 25 <210> SEQ ID NO 199 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 199 caccggaagc gactcgacat ggagg 25 <210> SEQ ID NO 200 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 200 caccggcgac tcgacatgga ggcga 25 <210> SEQ ID NO 201 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 201 aaactgtcga gtcgcttctc gattc 25 <210> SEQ ID NO 202 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 202 aaacgcaggg caacgcccag ggacc 25 <210> SEQ ID NO 203 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 203 aaacctgcag ggcaacgccc agggc 25 <210> SEQ ID NO 204 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 204 aaacattagt ttatcttccc acggc 25 <210> SEQ ID NO 205 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 205 aaacgggcgt tgccctgcag gggac 25 <210> SEQ ID NO 206 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 206 aaactaatcg agaagcgact cgacc 25 <210> SEQ ID NO 207 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 207 aaactacaag acgggaggca gcagc 25 <210> SEQ ID NO 208 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 208 aaacataaag gtattgcggc actcc 25 <210> SEQ ID NO 209 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 209 aaacttgctg caccaccaaa gtgtc 25 <210> SEQ ID NO 210 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 210 aaacgagttt tataccattt gagac 25 <210> SEQ ID NO 211 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 211 aaactctcga ttatgggcgg gattc 25 <210> SEQ ID NO 212 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 212 aaaccttctc gattatgggc gggac 25 <210> SEQ ID NO 213 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 213 aaacagtcgc ttctcgatta tgggc 25 <210> SEQ ID NO 214 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 214 aaactccatg tcgagtcgct tctcc 25 <210> SEQ ID NO 215 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 215 aaaccctcca tgtcgagtcg cttcc 25 <210> SEQ ID NO 216 <211> LENGTH: 25

<212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 216 aaactcgcct ccatgtcgag tcgcc 25 <210> SEQ ID NO 217 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 217 caccgacagg gttaatgtga agtcc 25 <210> SEQ ID NO 218 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 218 caccgtcccc ctctacattt aaagt 25 <210> SEQ ID NO 219 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 219 caccgcattt aaagttggtt taagt 25 <210> SEQ ID NO 220 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 220 caccgttaga aaatataaag aataa 25 <210> SEQ ID NO 221 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 221 caccgtaaat gcttactggt ttgaa 25 <210> SEQ ID NO 222 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 222 caccgtcctg ggtccagaaa aagat 25 <210> SEQ ID NO 223 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 223 caccgttggg tggtgagcat ctgtg 25 <210> SEQ ID NO 224 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 224 caccgcgggg agagtggaga aaaag 25 <210> SEQ ID NO 225 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 225 caccggttaa aactctttag acaac 25 <210> SEQ ID NO 226 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 226 caccggaaaa tccccactaa gatcc 25 <210> SEQ ID NO 227 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 227 aaacggactt cacattaacc ctgtc 25 <210> SEQ ID NO 228 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 228 aaacacttta aatgtagagg gggac 25 <210> SEQ ID NO 229 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 229 aaacacttaa accaacttta aatgc 25 <210> SEQ ID NO 230 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 230 aaacttattc tttatatttt ctaac 25 <210> SEQ ID NO 231 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 231 aaacttcaaa ccagtaagca tttac 25 <210> SEQ ID NO 232 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 232 aaacatcttt ttctggaccc aggac 25 <210> SEQ ID NO 233 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 233 aaaccacaga tgctcaccac ccaac 25 <210> SEQ ID NO 234 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 234 aaaccttttt ctccactctc cccgc 25 <210> SEQ ID NO 235 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 235 aaacgttgtc taaagagttt taacc 25 <210> SEQ ID NO 236 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 236 aaacggatct tagtggggat tttcc 25 <210> SEQ ID NO 237

<211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 237 agtagcagta atgaagctgg 20 <210> SEQ ID NO 238 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 238 atacccagac gagaaagctg 20 <210> SEQ ID NO 239 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 239 tacccagacg agaaagctga 20 <210> SEQ ID NO 240 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 240 ggtggtgagc atctgtgtgg 20 <210> SEQ ID NO 241 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 241 aaatgagaag aagaggcaca 20 <210> SEQ ID NO 242 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 242 cttgtggcct gggagagctg 20 <210> SEQ ID NO 243 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 243 gctgtagaag gagacagagc 20 <210> SEQ ID NO 244 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 244 gagctggttg ggaagacatg 20 <210> SEQ ID NO 245 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 245 ctggttggga agacatgggg 20 <210> SEQ ID NO 246 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 246 cgtgaggatg ggaaggaggg 20 <210> SEQ ID NO 247 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 247 atgcagagtc agcagaactg 20 <210> SEQ ID NO 248 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 248 aagacatcaa gcacagaagg 20 <210> SEQ ID NO 249 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 249 tcaagcacag aaggaggagg 20 <210> SEQ ID NO 250 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 250 aaccgtcaat aggcaaaggg 20 <210> SEQ ID NO 251 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 251 ccgtatttca gactgaatgg 20 <210> SEQ ID NO 252 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 252 gagaggacag gtgctacagg 20 <210> SEQ ID NO 253 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 253 aaccaaggaa gggcaggagg 20 <210> SEQ ID NO 254 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 254 gacctctggg tggagacaga 20 <210> SEQ ID NO 255 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 255 cagatgacca tgacaagcag 20 <210> SEQ ID NO 256 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 256 aacaccagtg agtagagcgg 20 <210> SEQ ID NO 257 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 257 aggaccttga agcacagaga 20

<210> SEQ ID NO 258 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 258 tacagaggca gactaaccca 20 <210> SEQ ID NO 259 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 259 acagaggcag actaacccag 20 <210> SEQ ID NO 260 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 260 taaatgacgt gctagacctg 20 <210> SEQ ID NO 261 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 261 agtaaccact caggacaggg 20 <210> SEQ ID NO 262 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 262 accacaaaac agaaacacca 20 <210> SEQ ID NO 263 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 263 gtttgaagac aagcctgagg 20 <210> SEQ ID NO 264 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 264 gctgaacccc aaaagacagg 20 <210> SEQ ID NO 265 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 265 gcagctgaga cacacaccag 20 <210> SEQ ID NO 266 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 266 aggacacccc aaagaagctg 20 <210> SEQ ID NO 267 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 267 ggacacccca aagaagctga 20 <210> SEQ ID NO 268 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 268 ccagtgcaat ggacagaaga 20 <210> SEQ ID NO 269 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 269 agaagaggga gcctgcaagt 20 <210> SEQ ID NO 270 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 270 gtgtttgggc cctagagcga 20 <210> SEQ ID NO 271 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 271 catgtgcctg gtgcaatgca 20 <210> SEQ ID NO 272 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 272 tacaaagagg aagataagtg 20 <210> SEQ ID NO 273 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 273 gtcacagaat acaccactag 20 <210> SEQ ID NO 274 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 274 gggttaccct ggacatggaa 20 <210> SEQ ID NO 275 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 275 catggaaggg tattcactcg 20 <210> SEQ ID NO 276 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 276 agagtggcct agacaggctg 20 <210> SEQ ID NO 277 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 277 catgctggac agctcggcag 20 <210> SEQ ID NO 278 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 278 agtgaaagaa gagaaaattc 20

<210> SEQ ID NO 279 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 279 tggtaagtct aagaaaccta 20 <210> SEQ ID NO 280 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 280 cccacagcct aaccacccta 20 <210> SEQ ID NO 281 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 281 aatatttcaa agccctaggg 20 <210> SEQ ID NO 282 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 282 gcactcggaa cagggtctgg 20 <210> SEQ ID NO 283 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 283 agataggagc tccaacagtg 20 <210> SEQ ID NO 284 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 284 aagttagagc agccaggaaa 20 <210> SEQ ID NO 285 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 285 tagagcagcc aggaaaggga 20 <210> SEQ ID NO 286 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 286 tgaataccct tccatgtcca 20 <210> SEQ ID NO 287 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 287 cctgcattgc accaggcaca 20 <210> SEQ ID NO 288 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 288 tctagggccc aaacacacct 20 <210> SEQ ID NO 289 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 289 tccctccatc tatcaaaagg 20 <210> SEQ ID NO 290 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 290 agccctgaga cagaagcagg 20 <210> SEQ ID NO 291 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 291 gccctgagac agaagcaggt 20 <210> SEQ ID NO 292 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 292 aggagatgca gtgatacgca 20 <210> SEQ ID NO 293 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 293 acaataccaa gggtatccgg 20 <210> SEQ ID NO 294 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 294 tgataaagaa aacaaagtga 20 <210> SEQ ID NO 295 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 295 aaagaaaaca aagtgaggga 20 <210> SEQ ID NO 296 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 296 gtggcaagtg gagaaattga 20 <210> SEQ ID NO 297 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 297 caagtggaga aattgaggga 20 <210> SEQ ID NO 298 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 298 gtggtgatga ttgcagctgg 20 <210> SEQ ID NO 299 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 299 ctatgtgcct gacacacagg 20

<210> SEQ ID NO 300 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 300 gggttggacc aggaaagagg 20 <210> SEQ ID NO 301 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 301 gatgcctgga aaaggaaaga 20 <210> SEQ ID NO 302 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 302 tagtatgcac ctgcaagagg 20 <210> SEQ ID NO 303 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 303 tatgcacctg caagaggcgg 20 <210> SEQ ID NO 304 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 304 aggggaagaa gagaagcaga 20 <210> SEQ ID NO 305 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 305 gctgaatcaa gagacaagcg 20 <210> SEQ ID NO 306 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 306 aagcaaataa atctcctggg 20 <210> SEQ ID NO 307 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 307 agatgagtgc tagagactgg 20 <210> SEQ ID NO 308 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 308 ctgatggttg agcacagcag 20 <210> SEQ ID NO 309 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 309 caaatggcca gcaagggtgg 20 <210> SEQ ID NO 310 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 310 gcagaacctg aggatatgga 20 <210> SEQ ID NO 311 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 311 aatacacaga atgaaaatag 20 <210> SEQ ID NO 312 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 312 ctggtgacta gaataggcag 20 <210> SEQ ID NO 313 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 313 tggtgactag aataggcagt 20 <210> SEQ ID NO 314 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 314 taaaagaatg tgaaaagatg 20 <210> SEQ ID NO 315 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 315 tcaggagttc aagaccaccc 20 <210> SEQ ID NO 316 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 316 tgtagtccca gttatgcagg 20 <210> SEQ ID NO 317 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 317 gggttcacac cacaaatgca 20 <210> SEQ ID NO 318 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 318 ggcaaatggc cagcaagggt 20 <210> SEQ ID NO 319 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 319 agaaaccaat cccaaagcaa 20 <210> SEQ ID NO 320 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 320

gccaaggaca ccaaaaccca 20 <210> SEQ ID NO 321 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 321 agtggtgata aggcaacagt 20 <210> SEQ ID NO 322 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 322 cctgagacag aagtattaag 20 <210> SEQ ID NO 323 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 323 aaggtcacac aatgaatagg 20 <210> SEQ ID NO 324 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 324 caccatacta gggaagaaga 20 <210> SEQ ID NO 325 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 325 aataccctgc ccttagtggg 20 <210> SEQ ID NO 326 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 326 ttagtggggg gtggagtggg 20 <210> SEQ ID NO 327 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 327 caataccctg cccttagtgg 20 <210> SEQ ID NO 328 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 328 gtggggggtg gagtgggggg 20 <210> SEQ ID NO 329 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 329 ggggggtgga gtggggggtg 20 <210> SEQ ID NO 330 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 330 ggggtggagt ggggggtggg 20 <210> SEQ ID NO 331 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 331 gggtggagtg gggggtgggg 20 <210> SEQ ID NO 332 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 332 gggggtgggg aaagacatcg 20 <210> SEQ ID NO 333 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 333 gcagctgtga attctgatag 20 <210> SEQ ID NO 334 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 334 gagatcagag aaaccagatg 20 <210> SEQ ID NO 335 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 335 tctatactga ttgcagccag 20 <210> SEQ ID NO 336 <211> LENGTH: 1722 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 336 atggcgcaac actcagatta ctccgacgat gaattttgtg ctgacaaact gtccaattat 60 tcatgcgata gcgacctcga aaacgcttcc acgtctgatg aagatagcag cgatgatgaa 120 gtaatggtga ggcctcgcac cctccgccgt cgccgcatca gctcttcgag ctctgattct 180 gaatccgata ttgagggtgg ccgcgaggag tggtcccacg tagacaatcc gccggtgctg 240 gaggacttcc taggccacca aggtctgaac actgacgcag taatcaacaa tatcgaagat 300 gcagttaaac tgtttatcgg tgacgatttc ttcgagtttc tggtggagga atctaaccgg 360 tactataacc agaatcgtaa taacttcaag ctctctaaaa agtctctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctc ggtctgatcg ttctgatggg ccaagttcgc 480 aaggatcgtc gtgacgacta ttggactacc gaaccgtgga cggaaactcc atactttggc 540 aagaccatga ctcgtgaccg tttccgtcag atctggaagg cctggcactt caataacaac 600 gctgacattg tcaacgagtc tgatcgtctg tgtaaggttc gccctgtgct ggattacttc 660 gttccaaaat tcattaacat ttacaaacca catcagcagc tgtccctgga tgagggcatc 720 gtgccgtggc gcggccgcct gttcttccgt gtctataatg ctggcaagat tgtgaagtac 780 ggtatcctgg ttcgcctgct gtgcgaaagc gacactggct acatctgtaa catggagatc 840 tactgcggcg agggcaaacg tctcctcgaa actatccaga ccgtcgtgtc tccatacacg 900 gattcctggt atcatattta catggataac tattataaca gcgtggctaa ctgtgaagct 960 ctgatgaaaa ataagttccg tatttgcggt actatccgta agaatcgtgg aattccgaaa 1020 gatttccaga ccatctccct gaaaaagggt gaaactaagt tcattcgcaa aaacgacatc 1080 ctcctgcaag tctggcagtc taaaaagcct gtatatctga tctcatctat tcacagcgct 1140 gaaatggaag aatctcagaa cattgatcgc acctccaaga aaaagatcgt caaaccgaat 1200 gcattgattg attacaacaa gcacatgaag ggcgttgatc gtgctgacca gtacctgtct 1260 tattactcta tcctgcgccg tactgtgaag tggactaaac gtctcgctat gtacatgatt 1320 aattgtgcgc tgttcaattc ttacgctgtg tataaaagcg tgcgtcagcg caaaatgggc 1380 tttaaaatgt tcctgaagca gacggctatt cactggctga ccgacgatat tccggaagat 1440 atggacattg tcccggatct ccagccggta ccgagcacca gcggtatgcg tgctaaacct 1500 ccgactagtg atccgccttg ccgtctgtct atggatatgc gtaagcatac cctgcaggca 1560 attgtgggct ctggcaaaaa gaaaaatatc ctgcgtcgtt gccgcgtatg ctctgtacac 1620 aaactgcgtt ctgagactcg ttatatgtgt aaattttgca atattccact ccacaagggt 1680 gcgtgcttcg agaagtacca tacgctgaag aactatctcg ag 1722

<210> SEQ ID NO 337 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 337 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 338 <211> LENGTH: 1719 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 338 atggcccagc acagcgacta ccccgacgac gagttcagag ccgataagct gagtaactac 60 agctgcgaca gcgacctgga aaacgccagc acatccgacg aggacagctc tgacgacgag 120 gtgatggtgc ggcccagaac cctgagacgg agaagaatca gcagctctag cagcgactct 180 gaatccgaca tcgagggcgg ccgggaagag tggagccacg tggacaaccc tcctgttctg 240 gaagattttc tgggccatca gggcctgaac accgacgccg tgatcaacaa catcgaggat 300 gccgtgaagc tgttcatagg agatgatttc tttgagttcc tggtcgagga atccaaccgc 360 tattacaacc agaatagaaa caacttcaag ctgagcaaga aaagcctgaa gtggaaggac 420 atcacccctc aggagatgaa aaagttcctg ggactgatcg ttctgatggg acaggtgcgg 480 aaggacagaa gggatgatta ctggacaacc gaaccttgga ccgagacccc ttactttggc 540 aagaccatga ccagagacag attcagacag atctggaaag cctggcactt caacaacaat 600 gctgatatcg tgaacgagtc tgatagactg tgtaaagtgc ggccagtgtt ggattacttc 660 gtgcctaagt tcatcaacat ctataagcct caccagcagc tgagcctgga tgaaggcatc 720 gtgccctggc ggggcagact gttcttcaga gtgtacaatg ctggcaagat cgtcaaatac 780 ggcatcctgg tgcgccttct gtgcgagagc gatacaggct acatctgtaa tatggaaatc 840 tactgcggcg agggcaaaag actgctggaa accatccaga ccgtcgtttc cccttatacc 900 gacagctggt accacatcta catggacaac tactacaatt ctgtggccaa ctgcgaggcc 960 ctgatgaaga acaagtttag aatctgcggc acaatcagaa aaaacagagg catccctaag 1020 gacttccaga ccatctctct gaagaagggc gaaaccaagt tcatcagaaa gaacgacatc 1080 ctgctccaag tgtggcagtc caagaaaccc gtgtacctga tcagcagcat ccatagcgcc 1140 gagatggaag aaagccagaa catcgacaga acaagcaaga agaagatcgt gaagcccaat 1200 gctctgatcg actacaacaa gcacatgaaa ggcgtggacc gggccgacca gtacctgtct 1260 tattactcta tcctgagaag aacagtgaaa tggaccaaga gactggccat gtacatgatc 1320 aattgcgccc tgttcaacag ctacgccgtg tacaagtccg tgcgacaaag aaaaatggga 1380 ttcaagatgt tcctgaagca gacagccatc cactggctga cagacgacat tcctgaggac 1440 atggacattg tgccagatct gcaacctgtg cccagcacct ctggtatgag agctaagcct 1500 cccaccagcg atcctccatg tagactgagc atggacatgc ggaagcacac cctgcaggcc 1560 atcgtcggca gcggcaagaa gaagaacatc cttagacggt gcagggtgtg cagcgtgcac 1620 aagctgcgga gcgagactcg gtacatgtgc aagttttgca acattcccct gcacaaggga 1680 gcctgcttcg agaagtacca caccctgaag aattactag 1719 <210> SEQ ID NO 339 <211> LENGTH: 1716 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 339 atgtcgcagc attcagacta tactcatgat gagttttgtg cagacaagtt gtccaattat 60 tcttgtgata gcgatcttga aaatgcgagt acaagtgatg aagattctag tgatgatgaa 120 gtaatggtgc gtcccaggac attgaggcga cgaagaattt cgagctccag ctctgactca 180 gagtcagata tagaaggcgg gagagaagaa tggtcgcatg ttgataatcc accggtctta 240 gaagattttt tagggcatca aggattaaac acagatgctg ttataaataa tatagaagat 300 gccgtgaaat tatttatcgg agatgatttt tttgaatttc ttgtagagga gtcaaacagg 360 tattataatc aaaataggaa taatttcaaa ctttcaaaaa aaagcctaaa gtggaaagat 420 ataacccctc aagagatgaa gaagttttta gggttaattg ttctcatggg acaggtgcgc 480 aaagatagaa gagatgacta ttggaccacg gagccatgga cggagacgcc atattttggt 540 aaaacgatga cgagagacag gttccgacag atatggaaag cttggcactt caataataat 600 gcggatatcg taaatgaatc agatagactt tgcaaagtga gaccagtact agattatttt 660 gtgcctaaat ttataaatat ttacaaacct catcagcaat tatcactaga tgaagggatc 720 gtaccttgga ggggaagatt attctttagg gtatataatg ctggcaagat cgttaaatat 780 ggaatattgg ttcgtttgtt gtgcgaaagt gatacaggat atatctgtaa catggaaatt 840 tattgcggcg aaggaaagcg attattggaa acgatacaaa cagtagtgtc tccatacact 900 gattcgtggt accatatata tatggacaat tattataata gcgtcgcaaa ttgtgaagca 960 cttatgaaaa acaaattcag aatatgtgga acaatccgga aaaatcgagg tatacctaaa 1020 gattttcaaa caatttcttt gaaaaaaggt gaaacaaaat ttataaggaa aaatgatata 1080 ttgttacaag tgtggcaatc aaaaaagcct gtatacctga tttcttcgat tcattctgcg 1140 gagatggaag aaagtcagaa tattgacaga acatcaaaaa agaaaattgt caaaccgaat 1200 gcactcattg actacaataa acatatgaaa ggtgttgacc gggccgacca atacctttca 1260 tattattcga tattgcggag gacggtcaaa tggacaaaaa ggttggcaat gtatatgata 1320 aattgcgcat tatttaattc ttatgcagtt tacaaatcag tgaggcaaag aaaaatgggt 1380 tttaaaatgt ttttgaaaca aacagctatc cactggttga cggatgatat tccagaggac 1440 atggacattg ttccagacct tcaaccagta ccgtctactt ctggaatgcg ggctaaacca 1500 cctacatctg atccaccatg caggctatcg atggacatga gaaagcatac gttacaggca 1560 attgtcggaa gtggaaaaaa gaaaaacatt ttgagaaggt gtcgcgtatg ttccgttcat 1620 aaattgcgca gtgagacacg ctacatgtgc aaattttgca atatacctct acataaaggg 1680 gcgtgttttg aaaaatatca tacgctaaaa aactat 1716 <210> SEQ ID NO 340 <211> LENGTH: 572 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 340 Met Ala Gln His Ser Asp Tyr Pro Asp Asp Glu Phe Arg Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Lys Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205

Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr 565 570 <210> SEQ ID NO 341 <211> LENGTH: 574 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 341 Met Ala Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Tyr Tyr Asn Gln Asn Arg Asn Asn 115 120 125 Phe Lys Leu Ser Lys Lys Ser Leu Lys Trp Lys Asp Ile Thr Pro Gln 130 135 140 Glu Met Lys Lys Phe Leu Gly Leu Ile Val Leu Met Gly Gln Val Arg 145 150 155 160 Lys Asp Arg Arg Asp Asp Tyr Trp Thr Thr Glu Pro Trp Thr Glu Thr 165 170 175 Pro Tyr Phe Gly Lys Thr Met Thr Arg Asp Arg Phe Arg Gln Ile Trp 180 185 190 Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val Asn Glu Ser Asp 195 200 205 Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe Val Pro Lys Phe 210 215 220 Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu Asp Glu Gly Ile 225 230 235 240 Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr Asn Ala Gly Lys 245 250 255 Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys Glu Ser Asp Thr 260 265 270 Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu Gly Lys Arg Leu 275 280 285 Leu Glu Thr Ile Gln Thr Val Val Ser Pro Tyr Thr Asp Ser Trp Tyr 290 295 300 His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn Cys Glu Ala 305 310 315 320 Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg Lys Asn Arg 325 330 335 Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys Gly Glu Thr 340 345 350 Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp Gln Ser Lys 355 360 365 Lys Pro Val Tyr Leu Ile Ser Ser Ile His Ser Ala Glu Met Glu Glu 370 375 380 Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys Pro Asn 385 390 395 400 Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg Ala Asp 405 410 415 Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Thr Val Lys Trp Thr 420 425 430 Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser Tyr 435 440 445 Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met Phe 450 455 460 Leu Lys Gln Thr Ala Ile His Trp Leu Thr Asp Asp Ile Pro Glu Asp 465 470 475 480 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 485 490 495 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 500 505 510 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 515 520 525 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 530 535 540 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 545 550 555 560 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn Tyr Leu Glu 565 570 <210> SEQ ID NO 342 <400> SEQUENCE: 342 000 <210> SEQ ID NO 343 <211> LENGTH: 507 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 343 Met Ser Gln His Ser Asp Tyr Ser Asp Asp Glu Phe Cys Ala Asp Lys 1 5 10 15 Leu Ser Asn Tyr Ser Cys Asp Ser Asp Leu Glu Asn Ala Ser Thr Ser 20 25 30 Asp Glu Asp Ser Ser Asp Asp Glu Val Met Val Arg Pro Arg Thr Leu 35 40 45 Arg Arg Arg Arg Ile Ser Ser Ser Ser Ser Asp Ser Glu Ser Asp Ile 50 55 60 Glu Gly Gly Arg Glu Glu Trp Ser His Val Asp Asn Pro Pro Val Leu 65 70 75 80 Glu Asp Phe Leu Gly His Gln Gly Leu Asn Thr Asp Ala Val Ile Asn 85 90 95 Asn Ile Glu Asp Ala Val Lys Leu Phe Ile Gly Asp Asp Phe Phe Glu 100 105 110 Phe Leu Val Glu Glu Ser Asn Arg Lys Thr Met Thr Arg Asp Arg Phe 115 120 125 Arg Gln Ile Trp Lys Ala Trp His Phe Asn Asn Asn Ala Asp Ile Val 130 135 140 Asn Glu Ser Asp Arg Leu Cys Lys Val Arg Pro Val Leu Asp Tyr Phe 145 150 155 160 Val Pro Lys Phe Ile Asn Ile Tyr Lys Pro His Gln Gln Leu Ser Leu 165 170 175 Asp Glu Gly Ile Val Pro Trp Arg Gly Arg Leu Phe Phe Arg Val Tyr 180 185 190 Asn Ala Gly Lys Ile Val Lys Tyr Gly Ile Leu Val Arg Leu Leu Cys 195 200 205 Glu Ser Asp Thr Gly Tyr Ile Cys Asn Met Glu Ile Tyr Cys Gly Glu 210 215 220 Gly Lys Arg Leu Leu Glu Thr Ile Gln Thr Trp Ser Pro Tyr Thr Asp 225 230 235 240 Ser Trp Tyr His Ile Tyr Met Asp Asn Tyr Tyr Asn Ser Val Ala Asn

245 250 255 Cys Glu Ala Leu Met Lys Asn Lys Phe Arg Ile Cys Gly Thr Ile Arg 260 265 270 Lys Asn Arg Gly Ile Pro Lys Asp Phe Gln Thr Ile Ser Leu Lys Lys 275 280 285 Gly Glu Thr Lys Phe Ile Arg Lys Asn Asp Ile Leu Leu Gln Val Trp 290 295 300 Gln Ser Lys Lys Pro Val Tyr Leu Ile Ser Ser His Ser Ala Glu Met 305 310 315 320 Glu Glu Ser Gln Asn Ile Asp Arg Thr Ser Lys Lys Lys Ile Val Lys 325 330 335 Pro Asn Ala Leu Ile Asp Tyr Asn Lys His Met Lys Gly Val Asp Arg 340 345 350 Ala Asp Gln Tyr Leu Ser Tyr Tyr Ser Ile Leu Arg Arg Trp Lys Trp 355 360 365 Thr Lys Arg Leu Ala Met Tyr Met Ile Asn Cys Ala Leu Phe Asn Ser 370 375 380 Tyr Ala Val Tyr Lys Ser Val Arg Gln Arg Lys Met Gly Phe Lys Met 385 390 395 400 Phe Leu Lys Gln Thr Ala His Trp Leu Thr Asp Asp Ile Pro Glu Asp 405 410 415 Met Asp Ile Val Pro Asp Leu Gln Pro Val Pro Ser Thr Ser Gly Met 420 425 430 Arg Ala Lys Pro Pro Thr Ser Asp Pro Pro Cys Arg Leu Ser Met Asp 435 440 445 Met Arg Lys His Thr Leu Gln Ala Ile Val Gly Ser Gly Lys Lys Lys 450 455 460 Asn Ile Leu Arg Arg Cys Arg Val Cys Ser Val His Lys Leu Arg Ser 465 470 475 480 Glu Thr Arg Tyr Met Cys Lys Phe Cys Asn Ile Pro Leu His Lys Gly 485 490 495 Ala Cys Phe Glu Lys Tyr His Thr Leu Lys Asn 500 505 <210> SEQ ID NO 344 <211> LENGTH: 153 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 344 cacttggatt gcgggaaacg agttaagtcg gctcgcgtga attgcgcgta ctccgcggga 60 gccgtcttaa ctcggttcat atagatttgc ggtggagtgc gggaaacgtg taaactcggg 120 ccgattgtaa ctgcgtatta ccaaatattt gtt 153 <210> SEQ ID NO 345 <211> LENGTH: 158 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 345 cacttgggtt gcgggaaacg agttaagtcg gctcgcgtga attgcgcgta ctccgcggga 60 gccgtcttaa actcggttca tatagatttg cggtggagtg cgggaaacgt tgtaaactcg 120 ggccgattgt aactgcgtat taccaaatat ttcatttc 158 <210> SEQ ID NO 346 <211> LENGTH: 181 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 346 aaatgtctgt gattgaataa attttcattt tttacacaag aaaccgaaaa tttcatttca 60 atcgaaccca tacttcaaaa gatataggca ttttaaacta actctgattt tgcgcgggaa 120 acctaaataa ttgcccgcgc catcttatat tttggcggga aattcacccg acaccgtagt 180 g 181 <210> SEQ ID NO 347 <211> LENGTH: 136 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 347 aaacgttgta aactcgggcc gattgtaact gcgtattacc aaatatttca tttcaatcga 60 acccatactt aaaagatata ggcattttaa cgcgccatct tatattttgg cgggaaattc 120 acccgacacc gtagtg 136 <210> SEQ ID NO 348 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(6) <223> OTHER INFORMATION: Xaa can be any naturally occurring amino acid; SEQ ID NO: 348 corresponds to the sequence K(K/R)X(K/R) <400> SEQUENCE: 348 Lys Lys Arg Xaa Lys Arg 1 5 <210> SEQ ID NO 349 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(7) <223> OTHER INFORMATION: Xaa can be any naturally occurring amino acid; SEQ ID NO: 349 corresponds to the sequence (K/R)(K/R)X10- 12(K/R)3/5 <400> SEQUENCE: 349 Lys Arg Lys Arg Xaa Lys Arg 1 5 <210> SEQ ID NO 350 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 350 Pro Ala Ala Lys Arg Val Lys Leu Asp 1 5 <210> SEQ ID NO 351 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 351 Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys 1 5 10 15 <210> SEQ ID NO 352 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 352 Pro Lys Lys Lys Arg Lys Val 1 5 <210> SEQ ID NO 353 <211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 353 Asp Pro Lys Lys Lys Arg Lys Val Asp Pro Lys Lys Lys Arg Lys Val 1 5 10 15 Asp Pro Lys Lys Lys Arg Lys Val 20 <210> SEQ ID NO 354 <400> SEQUENCE: 354 000 <210> SEQ ID NO 355 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 355 Asn His Asn His His Asp His Asp Asn His Asn His His Asp His Asp 1 5 10 15 Asn Gly Asn His Asn Ile His Asp His Asp Asn Ile His Asp Asn Gly 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 356 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 356 Asn His Asn Ile Asn Ile Asn His Asn His His Asp His Asp Asn Gly 1 5 10 15 Asn His Asn His His Asp His Asp Asn His Asn His His Asp His Asp 20 25 30

Asn Gly Asn His 35 <210> SEQ ID NO 357 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 357 Asn His Asn Ile Asn His His Asp Asn Ile His Asp Asn Gly Asn His 1 5 10 15 Asn Ile Asn Ile Asn His Asn His His Asp His Asp Asn Gly Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 358 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 358 His Asp His Asp Asn Ile His Asp Asn Gly Asn His Asn Ile Asn His 1 5 10 15 His Asp Asn Ile His Asp Asn Gly Asn His Asn Ile Asn Ile Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 359 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 359 Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp His Asp Asn Ile 1 5 10 15 His Asp Asn Gly Asn His Asn Ile Asn His His Asp Asn Ile His Asp 20 25 30 Asn Gly Asn His 35 <210> SEQ ID NO 360 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 360 Asn His Asn His Asn His Asn His Asn Ile Asn Ile Asn Ile Asn Ile 1 5 10 15 Asn Gly Asn His Asn Ile His Asp His Asp His Asp Asn Ile Asn Ile 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 361 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 361 Asn Ile Asn His Asn His Asn Ile His Asp Asn Ile Asn His Asn Gly 1 5 10 15 Asn His Asn His Asn His Asn His Asn Ile Asn Ile Asn Ile Asn Ile 20 25 30 Asn Gly Asn His 35 <210> SEQ ID NO 362 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 362 His Asp His Asp Asn Ile Asn His Asn His Asn His Asn Ile His Asp 1 5 10 15 Asn Ile His Asp Asn His Asn His Asn Gly Asn His His Asp Asn Gly 20 25 30 Asn Ile Asn His 35 <210> SEQ ID NO 363 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 363 His Asp Asn Ile Asn His Asn Ile Asn His His Asp His Asp Asn Ile 1 5 10 15 Asn His Asn His Asn Ile Asn His Asn Gly His Asp His Asp Asn Gly 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 364 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 364 His Asp His Asp Asn Gly Asn Gly His Asp Asn Ile Asn His Asn Ile 1 5 10 15 Asn His His Asp His Asp Asn Ile Asn His Asn His Asn Ile Asn His 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 365 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 365 His Asp His Asp Asn Gly His Asp His Asp Asn Gly Asn Gly His Asp 1 5 10 15 Asn Ile Asn His Asn Ile Asn His His Asp His Asp Asn Ile Asn His 20 25 30 Asn His Asn Ile 35 <210> SEQ ID NO 366 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 366 His Asp His Asp Asn Ile Asn His His Asp His Asp His Asp His Asp 1 5 10 15 Asn Gly His Asp His Asp Asn Gly His Asp His Asp Asn Gly Asn Gly 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 367 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 367 His Asp His Asp Asn His Asn Ile Asn His His Asp Asn Gly Asn Gly 1 5 10 15 Asn His Asn Ile His Asp His Asp His Asp Asn Gly Asn Gly Asn His 20 25 30 Asn His Asn Ile 35 <210> SEQ ID NO 368 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 368 Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp His Asp Asn His 1 5 10 15 Asn Ile Asn His His Asp Asn Gly Asn Gly Asn His Asn Ile His Asp 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 369 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 369 Asn His Asn His Asn His Asn His Asn Gly Asn His Asn His Asn Gly 1 5 10 15 Asn Gly Asn Gly His Asp His Asp Asn His Asn Ile Asn His His Asp 20 25 30 Asn Gly Asn Gly 35

<210> SEQ ID NO 370 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 370 His Asp Asn Gly Asn His His Asp Asn Gly Asn His Asn His Asn His 1 5 10 15 Asn His Asn Gly Asn His Asn His Asn Gly Asn Gly Asn Gly His Asp 20 25 30 His Asp Asn His 35 <210> SEQ ID NO 371 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 371 Asn His His Asp Asn Ile Asn His Asn Ile Asn His Asn Gly Asn Ile 1 5 10 15 Asn Gly His Asp Asn Gly Asn His His Asp Asn Gly Asn His Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 372 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 372 His Asp His Asp Asn Ile Asn Ile Asn Gly His Asp His Asp His Asp 1 5 10 15 His Asp Asn Gly His Asp Asn Ile Asn His Asn Gly 20 25 <210> SEQ ID NO 373 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 373 His Asp Asn Ile Asn His Asn Gly Asn His His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn His Asn Gly Asn His Asn His Asn Ile Asn Ile 20 25 30 <210> SEQ ID NO 374 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 374 Asn His Asn Ile Asn Ile Asn Ile His Asp Asn Ile Asn Gly His Asp 1 5 10 15 His Asp Asn His Asn His His Asp Asn His Asn Ile His Asp Asn Gly 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 375 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 375 His Asp Asn His His Asp His Asp His Asp His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn Ile Asn Ile Asn Gly His Asp Asn Gly Asn Gly Asn Ile 20 25 30 His Asp Asn Ile 35 <210> SEQ ID NO 376 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 376 His Asp Asn Ile Asn Ile Asn Ile Asn Gly His Asp Asn Gly Asn Gly 1 5 10 15 Asn Ile His Asp Asn Ile Asn His His Asp Asn Gly Asn His His Asp 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 377 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 377 His Asp Asn Gly Asn Gly Asn Ile His Asp Asn Ile Asn His His Asp 1 5 10 15 Asn Gly Asn His His Asp Asn Gly His Asp Asn Ile His Asp Asn Gly 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 378 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 378 Asn Ile His Asp Asn Ile Asn His His Asp Asn Gly Asn His His Asp 1 5 10 15 Asn Gly His Asp Asn Ile His Asp Asn Gly His Asp His Asp His Asp 20 25 30 His Asp Asn Gly 35 <210> SEQ ID NO 379 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 379 Asn His His Asp Asn Gly His Asp Asn Ile His Asp Asn Gly His Asp 1 5 10 15 His Asp His Asp His Asp Asn Gly Asn His His Asp Asn Ile Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 380 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 380 His Asp His Asp His Asp His Asp Asn Gly Asn His His Asp Asn Ile 1 5 10 15 Asn His Asn His Asn His His Asp Asn Ile Asn Ile His Asp Asn His 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 381 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 381 Asn His His Asp Asn Ile Asn His Asn His Asn His His Asp Asn Ile 1 5 10 15 Asn Ile His Asp Asn His His Asp His Asp His Asp Asn Ile Asn His 20 25 30 Asn His Asn His 35 <210> SEQ ID NO 382 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 382 His Asp Asn Gly His Asp Asn His Asn Ile Asn Gly Asn Gly Asn Ile 1 5 10 15 Asn Gly Asn His Asn His Asn His His Asp Asn His Asn His Asn His 20 25 30 Asn Ile Asn Gly 35 <210> SEQ ID NO 383 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 383

His Asp Asn His His Asp Asn Gly Asn Gly His Asp Asn Gly His Asp 1 5 10 15 Asn His Asn Ile Asn Gly Asn Gly Asn Ile Asn Gly Asn His Asn His 20 25 30 Asn His His Asp 35 <210> SEQ ID NO 384 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 384 Asn His Asn Gly His Asp Asn His Asn Ile Asn His Asn Gly His Asp 1 5 10 15 Asn His His Asp Asn Gly Asn Gly His Asp Asn Gly His Asp Asn His 20 25 30 Asn Ile Asn Gly 35 <210> SEQ ID NO 385 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 385 His Asp His Asp Asn Ile Asn Gly Asn His Asn Gly His Asp Asn His 1 5 10 15 Asn Ile Asn His Asn Gly His Asp Asn His His Asp Asn Gly Asn Gly 20 25 30 His Asp Asn Gly 35 <210> SEQ ID NO 386 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 386 His Asp Asn His His Asp His Asp Asn Gly His Asp His Asp Asn Ile 1 5 10 15 Asn Gly Asn His Asn Gly His Asp Asn His Asn Ile Asn His Asn Gly 20 25 30 His Asp Asn His 35 <210> SEQ ID NO 387 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 387 His Asp Asn His Asn Gly His Asp Asn Ile Asn Gly His Asp Asn His 1 5 10 15 His Asp His Asp Asn Gly His Asp His Asp Asn Ile Asn Gly Asn His 20 25 30 Asn Gly His Asp 35 <210> SEQ ID NO 388 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 388 Asn His Asn Ile Asn Gly His Asp Asn Gly His Asp Asn His Asn Gly 1 5 10 15 His Asp Asn Ile Asn Gly His Asp Asn His His Asp His Asp Asn Gly 20 25 30 His Asp His Asp 35 <210> SEQ ID NO 389 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 389 Asn His His Asp Asn Gly Asn Gly His Asp Asn Ile Asn His His Asp 1 5 10 15 Asn Gly Asn Gly His Asp His Asp Asn Gly Asn Ile 20 25 <210> SEQ ID NO 390 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 390 His Asp Asn Gly Asn Lys Asn Gly Asn His Asn Ile Asn Gly His Asp 1 5 10 15 Asn Ile Asn Gly Asn His His Asp His Asp Asn Ile 20 25 <210> SEQ ID NO 391 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 391 Asn Ile His Asp Asn Ile Asn Asn Asn Gly Asn Asn Asn Asn Asn Gly 1 5 10 15 Asn Ile His Asp Asn Ile His Asp Asn Ile His Asp His Asp Asn Gly 20 25 30 <210> SEQ ID NO 392 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 392 His Asp His Asp Asn Ile His Asp His Asp His Asp His Asp His Asp 1 5 10 15 His Asp Asn Ile His Asp Asn Gly Asn Ile Asn Ile Asn Asn 20 25 30 <210> SEQ ID NO 393 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 393 His Asp Asn Ile Asn Gly Asn Gly Asn Asn Asn Asn His Asp His Asp 1 5 10 15 Asn Asn Asn Asn Asn Asn His Asp Asn Ile His Asp 20 25 <210> SEQ ID NO 394 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 394 Asn Asn His Asp Asn Gly Asn Gly Asn Asn Asn Ile Asn Ile His Asp 1 5 10 15 His Asp His Asp Asn Ile Asn Asn Asn Asn Asn Ile Asn Asn Asn Ile 20 25 30 <210> SEQ ID NO 395 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 395 Asn Ile His Asp Asn Ile His Asp His Asp His Asp Asn Asn Asn Ile 1 5 10 15 Asn Gly His Asp His Asp Asn Ile His Asp Asn Gly Asn Asn Asn Asn 20 25 30 Asn Asn <210> SEQ ID NO 396 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 396 Asn Asn His Asp Asn Gly Asn Asn His Asp Asn Ile Asn Gly His Asp 1 5 10 15 Asn Ile Asn Ile His Asp His Asp His Asp His Asp 20 25 <210> SEQ ID NO 397 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 397 Asn Asn Asn Asn His Asp Asn Ile His Asp Asn Asn Asn Ile Asn Ile 1 5 10 15 Asn Ile His Asp Asn Ile His Asp His Asp His Asp Asn Gly His Asp 20 25 30 His Asp

<210> SEQ ID NO 398 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 398 Asn Asn Asn Asn Asn Gly Asn Asn Asn Asn His Asp Asn Gly His Asp 1 5 10 15 Asn Ile Asn Gly Asn Asn His Asp His Asp Asn Gly Asn Asn 20 25 30 <210> SEQ ID NO 399 <211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 399 Asn Asn Asn Ile Asn Gly Asn Gly Asn Gly Asn Asn His Asp Asn Ile 1 5 10 15 His Asp Asn Ile Asn Asn His Asp Asn Gly His Asp Asn Ile Asn Gly 20 25 30 <210> SEQ ID NO 400 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 400 Asn Ile Asn Ile Asn His His Asp Asn Gly His Asp Asn Gly Asn His 1 5 10 15 Asn Ile Asn His Asn His Asn Ile Asn His His Asp 20 25 <210> SEQ ID NO 401 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 401 His Asp His Asp His Asp Asn Gly Asn Ile Asn Lys His Asp Asn Gly 1 5 10 15 Asn His Asn Gly His Asp His Asp His Asp His Asp 20 25 <210> SEQ ID NO 402 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 402 Asn His His Asp His Asp Asn Gly Asn Ile Asn His His Asp Asn Ile 1 5 10 15 Asn Gly Asn His His Asp Asn Gly Asn Ile Asn His 20 25 <210> SEQ ID NO 403 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 403 Asn Ile Asn Gly Asn His Asn His Asn His His Asp Asn Gly Asn Gly 1 5 10 15 His Asp Asn Ile His Asp Asn His Asn His Asn Ile Asn Gly 20 25 30 <210> SEQ ID NO 404 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 404 Asn His Asn Ile Asn Ile Asn Ile His Asp Asn Gly Asn Ile Asn Gly 1 5 10 15 Asn His His Asp His Asp Asn Gly Asn His His Asp 20 25 <210> SEQ ID NO 405 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 405 Asn His His Asp Asn Ile His Asp His Asp Asn Ile Asn Gly Asn Gly 1 5 10 15 Asn His His Asp Asn Gly His Asp His Asp His Asp 20 25 <210> SEQ ID NO 406 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 406 Asn His Asn Ile His Asp Asn Ile Asn Gly Asn His His Asp Asn Ile 1 5 10 15 Asn Ile His Asp Asn Gly His Asp Asn Ile Asn His 20 25 <210> SEQ ID NO 407 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 407 Asn Ile His Asp Asn Ile His Asp His Asp Asn Ile His Asp Asn Gly 1 5 10 15 Asn Ile Asn His Asn His Asn His Asn His Asn Gly 20 25 <210> SEQ ID NO 408 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 408 Asn His Asn Gly His Asp Asn Gly Asn His His Asp Asn Gly Asn Ile 1 5 10 15 Asn His Asn Ile His Asp Asn Ile Asn His Asn His 20 25 <210> SEQ ID NO 409 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 409 Asn His Asn His His Asp His Asp Asn Gly Asn Ile Asn His Asn Ile 1 5 10 15 His Asp Asn Ile Asn His Asn His His Asp Asn Gly Asn His 20 25 30 <210> SEQ ID NO 410 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 410 Asn His Asn Ile Asn His Asn His His Asp Asn Ile Asn Gly Asn Gly 1 5 10 15 His Asp Asn Gly Asn Gly Asn Ile Asn Gly His Asp Asn His 20 25 30 <210> SEQ ID NO 411 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 411 Asn Asn His Asp His Asp Asn Gly Asn Asn Asn Asn Asn Ile Asn Ile 1 5 10 15 Asn Ile His Asp Asn Asn Asn Gly Asn Gly His Asp His Asp 20 25 30 <210> SEQ ID NO 412 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 412 Asn Asn Asn Gly Asn Asn His Asp Asn Gly His Asp Asn Gly Asn Asn 1 5 10 15 Asn Ile His Asp Asn Ile Asn Ile Asn Gly Asn Ile 20 25 <210> SEQ ID NO 413 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 413

Asn Asn Asn Gly Asn Gly Asn Gly Asn Gly Asn Asn His Asp Asn Ile 1 5 10 15 Asn Asn His Asp His Asp Asn Gly His Asp His Asp 20 25 <210> SEQ ID NO 414 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 414 Asn Ile His Asp Asn Ile Asn Asn His Asp Asn Gly Asn Asn Asn Gly 1 5 10 15 Asn Asn Asn Asn Asn Ile Asn Ile His Asp Asn Asn Asn Gly 20 25 30 <210> SEQ ID NO 415 <211> LENGTH: 36 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 415 His Asp Asn Ile Asn Ile Asn Asn Asn Ile His Asp His Asp Asn Asn 1 5 10 15 Asn Ile Asn Asn His Asp Asn Ile His Asp Asn Gly Asn Asn His Asp 20 25 30 Asn Gly Asn Asn 35 <210> SEQ ID NO 416 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 416 His Asp Asn Gly Asn Ile Asn Gly His Asp His Asp His Asp Asn Ile 1 5 10 15 Asn Ile Asn Ile Asn Ile His Asp Asn Gly His Asp Asn Gly 20 25 30 <210> SEQ ID NO 417 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 417 Asn His Asn Ile Asn Ile Asn Ile Asn Ile Asn Ile His Asp Asn Gly 1 5 10 15 Asn Ile Asn Gly Asn His Asn Gly Asn Ile Asn Gly 20 25 <210> SEQ ID NO 418 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 418 Asn Ile Asn His Asn His His Asp Asn Ile Asn His Asn His His Asp 1 5 10 15 Asn Gly Asn His Asn His Asn Gly Asn Gly Asn His Asn Ile 20 25 30 <210> SEQ ID NO 419 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 419 His Asp Asn Ile Asn Ile Asn Gly Asn Ile His Asp Asn Ile Asn Ile 1 5 10 15 His Asp His Asp Asn Ile His Asp Asn Asn His Asp 20 25 <210> SEQ ID NO 420 <211> LENGTH: 30 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 420 Asn Ile Asn Gly Asn Asn Asn Ile His Asp Asn Asn Asn Asn Asn Ile 1 5 10 15 His Asp Asn Gly His Asp Asn Ile Asn Ile His Asp Asn Gly 20 25 30 <210> SEQ ID NO 421 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 421 His Asp Asn Ile His Asp Asn Ile Asn Ile His Asp Asn Ile Asn Gly 1 5 10 15 Asn Gly Asn Gly Asn Asn Asn Gly Asn Ile Asn Ile 20 25 <210> SEQ ID NO 422 <211> LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 422 Asn Ile Asn Gly Asn Gly Asn Gly His Asp His Asp Asn Ile Asn Asn 1 5 10 15 Asn Gly Asn Asn His Asp Asn Ile His Asp Asn Ile 20 25 <210> SEQ ID NO 423 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 423 ggcggatctg gcggtagtgc tgagtattgt ctgagttacg aaacggaaat actcacggtt 60 gagtatgggc ttcttccaat tggcaaaatc gttgaaaagc gcatagagtg tacggtgtat 120 tccgtcgata acaacggtaa tatctacacc cagccggtag ctcagtggca cgaccgaggc 180 gaacaggaag tgttcgagta ttgcttggaa gatggctccc ttatccgcgc cactaaagac 240 cataagttta tgacggttga cgggcagatg ctgcctatag acgaaatatt tgagagagag 300 ctggacttga tgagagtcga taatctgcca aat 333 <210> SEQ ID NO 424 <211> LENGTH: 180 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 424 ggcggatctg gcggtagtgg gggttccgga tccataaaga tagctactag gaaatatctt 60 ggcaaacaaa acgtctatga cataggagtt gagcgagatc acaattttgc tttgaagaat 120 gggttcatcg cgtctaattg cttcaacgct agcggcgggt caggaggctc tggtggaagc 180 <210> SEQ ID NO 425 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 425 aatcgagaag cgactcgaca 20 <210> SEQ ID NO 426 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 426 tgccctgcag gggagtgagc 20 <210> SEQ ID NO 427 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 427 gaagcgactc gacatggagg 20 <210> SEQ ID NO 428 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Sequence <400> SEQUENCE: 428 cctgcagggg agtgagcagc 20

Claims

1.-151. (canceled)

152. A composition comprising a nucleic acid encoding a transposase enzyme, wherein the transposase enzyme comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 2 and has an non-polar aliphatic amino acid at position 2 of SEQ ID NO: 2, or a position corresponding thereto.

153. The composition of claim 152, wherein the non-polar aliphatic amino acid is selected from alanine (A), glycine (G), valine (V), leucine (L), isoleucine (I), and proline (P).

154. The composition of claim 153, wherein the non-polar aliphatic amino acid is alanine (A).

155. The composition of claim 152, wherein the transposase enzyme further comprises a substitution S8X.sub.1, wherein X.sub.1 is selected from alanine (A), glycine (G), valine (V), leucine (L), isoleucine (I), and proline (P), or a substitution corresponding thereto.

156. The composition of claim 155, wherein X.sub.1 is proline (P).

157. The composition of claim 152, wherein the transposase enzyme further comprises a substitution C13RX.sub.2, wherein X.sub.2 is selected from lysine (K), arginine (R), and histidine (H), or a substitution corresponding thereto.

158. The composition of claim 157, wherein X.sub.2 is arginine (R).

159. The composition of claim 152, wherein the transposase enzyme further comprises a substitution N125X.sub.3, wherein X.sub.3 is selected from is selected from lysine (K), arginine (R), and histidine (H), or a substitution corresponding thereto.

160. The composition of claim 159, wherein X.sub.3 is lysine (K).

161. The composition of claim 152, wherein the transposase enzyme further comprises two or more of substitutions S8P, C13R, and N125K, or a substitution corresponding thereto.

162. The composition of claim 152, wherein the transposase enzyme does not have additional amino acid residues at the C terminus relative to SEQ ID NO: 2.

163. The composition of claim 152, wherein the transposase enzyme comprises an amino acid sequence having at least 97% identity to SEQ ID NO: 2.

164. The composition of claim 152, wherein the transposase enzyme comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 2.

165. The composition of claim 152, further comprising a transcription activator-like effector (TALE) DNA binding domain (DBD), or a nuclease-deficient Cas9 (dCas9)/gRNA connected to the transposase enzyme.

166. The composition of claim 165, wherein the transposase enzyme is capable of inserting a transposon at a TA dinucleotide site or a TTAA (SEQ ID NO: 1) tetranucleotide site in a genomic safe harbor site (GSHS) of a nucleic acid molecule.

167. The composition of claim 166, wherein the TALE DBD or dCas9/gRNA is suitable for directing the transposase enzyme to the GSHS sequence.

168. The composition of claim 166, wherein the GSHS is selected from adeno-associated virus site 1 (AAVS1), chemokine (C-C motif) receptor 5 (CCR5) gene, HIV-1 coreceptor, and human Rosa26 locus.

169. The composition of claim 152, wherein the nucleic acid is co-formulated with a nucleic acid encoding a transposon.

170. The composition of claim 169, wherein the composition is in the form of a lipid nanoparticle (LNP).

171. A composition comprising the transposase enzyme polypeptide encoded by the nucleic acid of claim 152.

172. A method for inserting a gene into the genome of a cell, comprising contacting a cell with the composition of claim 169.

173. A method for inserting a gene into the genome of a cell, comprising contacting a cell with the composition of claim 170.

174. A composition comprising a first nucleic acid encoding a transposase enzyme and a DNA binding domain and a second nucleic acid encoding a transposon, wherein the transposase enzyme comprises an amino acid sequence having at least 97% sequence identity to SEQ ID NO: 2 and comprises two or more of substitutions of S8P, C13R, and N125K, or substitutions corresponding thereto, wherein the transposase enzyme comprises is operatively linked to the DNA binding domain, and wherein the first nucleic acid and second nucleic acid are contained in a LNP.

175. The composition of claim 174, wherein the DNA binding domain is a TALE DBD.

176. The composition of claim 174, wherein the DNA binding domain is a dCas9/gRNA.

177. The composition of claim 174, wherein the transposase enzyme does not have additional amino acid residues at the C terminus relative to SEQ ID NO: 2.

178. The composition of claim 177, wherein the substitutions are S8P and C13R, or substitutions corresponding thereto.

179. The composition of claim 175, wherein the transposase enzyme does not have additional amino acid residues at the C terminus relative to SEQ ID NO: 2.

180. The composition of claim 179, wherein the substitutions are S8P and C13R, or substitutions corresponding thereto.